Neuroimmune Mechanisms in Traumatic Brain Injury and Cancer: Parallel Courses or Existence in Different Orbits

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript reviewing "Traumatic Brain Injury and Cancer: The Intersection of Inflammation and T-Cell Exhaustion"-presents a very interesting paradigm. The immunosuppressive microenvironment that prevails in neoplasia and traumatic brain injury certainly has some parallel and presence of MDSC during both these processes mark the underlying inflammatory circuit. However, few minor points needed to be addressed by authors prior publication.

1. Authors have briefly mentioned MDSC but did not detail which subpopulation dominates TBI and particularly malignancies of brain. As authors are aware G-MDSC and M-MDSC play distinct role in inflammation and their distribution varies, brief discussion regarding these aspects will shed more light.
2. Recently it has been reported that SSRIs such as fluoxetine and citalopram exhibits T cell modulation and MDSC function, especially in neoplastic condition-can authors shed some light on possible use of SSRIs in management of immunosuppressive microenvironment in TBI and brain malignancies?  

Author Response

Dear Reviewer,

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in track changes in the re-submitted files.

Below are the answers and clarifications to your questions and comments.

Comments 1: Authors have briefly mentioned MDSC but did not detail which subpopulation dominates TBI and particularly malignancies of brain. As authors are aware G-MDSC and M-MDSC play distinct role in inflammation and their distribution varies, brief discussion regarding these aspects will shed more light.

Response 1: Thank you for your comment. We've added information about G-MDSCs and M-MDSCs to section 2.1. "The Immune System in Traumatic Brain Injury", lines 139-152

Regarding brain tumors, gliomas exhibit mechanisms that are largely similar to those occurring in tumors at other sites. In addition to MDSCs, tumor-associated macrophages and regulatory T-cells are involved in the formation of an immunosuppressive tumor microenvironment [Mi Y, Guo N, Luan J, Cheng J, 2020]. For this reason, we do not discuss brain tumors separately in this review.

However, there are data demonstrating an increase in CD14⁺ MDSCs, defined as M-MDSCs, and CD15⁺ MDSCs, defined as G-MDSCs (PMN-MDSCs), in the blood. CD15⁺ MDSCs predominated in tumor tissue [Gielen PR, Schulte BM, Kers-Rebel ED, 2015]. This is consistent with the results of other studies assessing different MDSC subpopulations in malignant brain tumors [Raychaudhuri B, Rayman P, Ireland J, Ko J, 2011; Dubinski D, Wölfer J, Hasselblatt M, 2016].

References:

1. Mi Y, Guo N, Luan J, Cheng J, Hu Z, Jiang P, Jin W, Gao X. The Emerging Role of Myeloid-Derived Suppressor Cells in the Glioma Immune Suppressive Microenvironment. Front Immunol. 2020 Apr 24;11:737. doi: 10.3389/fimmu.2020.00737. PMID: 32391020; PMCID: PMC7193311.
2. Gielen PR, Schulte BM, Kers-Rebel ED, Verrijp K, Petersen-Baltussen HM, ter Laan M, Wesseling P, Adema GJ. Increase in both CD14-positive and CD15-positive myeloid-derived suppressor cell subpopulations in the blood of patients with glioma but predominance of CD15-positive myeloid-derived suppressor cells in glioma tissue. J Neuropathol Exp Neurol. 2015
3. Raychaudhuri B, Rayman P, Ireland J, Ko J, Rini B, Borden EC, Garcia J, Vogelbaum MA, Finke J. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol. 2011 Jun;13(6):591-9. doi: 10.1093/neuonc/nor042. PMID: 21636707; PMCID: PMC3107102.
4. Dubinski D, Wölfer J, Hasselblatt M, Schneider-Hohendorf T, Bogdahn U, Stummer W, Wiendl H, Grauer OM. CD4+ T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. Neuro Oncol. 2016 Jun;18(6):807-18. doi: 10.1093/neuonc/nov280. Epub 2015 Nov 17. PMID: 26578623; PMCID: PMC4864257. 

Comments 2: Recently it has been reported that SSRIs such as fluoxetine and citalopram exhibits T cell modulation and MDSC function, especially in neoplastic condition-can authors shed some light on possible use of SSRIs in management of immunosuppressive microenvironment in TBI and brain malignancies?

Response 2: Thank you fot the interesting comment. Indeed, given the importance of the tumor microenvironment in metastasis and T-cell exhaustion, its modulation may be one option for combating the latter. The SSRI fluoxetine exhibited immunomodulatory properties, increasing the number of activated T-cells and reducing the number of MDSCs in the tumor microenvironment in sarcoma [Mahanti K, Saha J, Sarkar D, 2025]. Citalopram by modulating the response of tumor-associated macrophages via C5aR1, exhibited antitumor properties in experimental models of hepatocellular carcinoma [F. Dong, S. Zhang, K. Song, L. Jiang, 2025]. Moreover, psychotropic drugs enhanced the effect of immunotherapy [Schneider MA, Heeb L, Beffinger MM, Pantelyushin S, 2021].

Studies in patients have shown that fluoxetine [Kofod J, Elfving B, Nielsen EH, 2022] and escitalopram reduced the concentration of proinflammatory IL-1β (fluoxetine, escitalopram) and IL-5 (fluoxetine) in peripheral blood [Song C, Halbreich U, Han C, 2009]. Fluoxetine also reduced neuroinflammation in the subarachnoid hemorrhage model in rats. At a dose of 10 mg/kg, it (fluoxetine) reduced the number of Iba1⁺ and MPO⁺ cells, reduced MMP-9 expression in the ipsilateral cerebral cortex, and the amount of mRNA for proinflammatory cytokines TNF-α, IL-1β, and IL-6 [Liu FY, Cai J, Wang C, Ruan W, 2018]. However, when searching databases, we were unable to find information on how MDSCs modulate neuroinflammation. This is likely due to their protective role in nervous system injury, which has been demonstrated by several authors [Hosomi S, Koyama Y, Watabe T, 2019; Saiwai H, Kumamaru H, Ohkawa Y, 2013].

It should also be noted that most studies examine the anti-inflammatory potential of SSRIs in the context of treating depression, including those associated with TBI. No registered clinical trials were found for the search queries "Neuroinflammation + SSRIs" or "Traumatic brain injury + SSRIs" on Clinical Trials.

References:

1. Mahanti K, Saha J, Sarkar D, Pramanik A, Das D, Mondal P, Mahato M, Bhattacharyya S. Selective Serotonin Reuptake Inhibitor Fluoxetine Alters Gene Expression Patterns of Sarcoma and Significantly Reduces Tumor Load through Modulation of the Tumor Microenvironment and Restoration of the Host Antitumor Immune System. ACS Pharmacol Transl Sci. 2025 Jun 12;8(7):2132-2152. doi: 10.1021/acsptsci.5c00199. PMID: 40672680; PMCID: PMC12260934.
2. F Dong, S. Zhang, K. Song, L. Jiang, L. Hu, Q. Li, X.-L. Zhang, J. Li, M. Feng, Zhi-Wei Cai, Hong-Fei Yao, Rong-Kun Li, Hui Li, Jie Chen, Xiaona Hu, Jiaofeng Wang, Chongyi Jiang, Helen He Zhu, Cun Wang, Lin-Tai Da, Zhi-Gang Zhang, Zhijun Bao, Xu Wang, Shu-Heng Jiang (2025) Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+ TAMs and CD8+ T cells eLife 14:RP103016 https://doi.org/10.7554/eLife.103016.2
3. Qianyu Jing, Yujie Nie, Xiangyan Zhang, Lan Zhu, Huan Gui, et al. Antidepressants Combined with Immunotherapy for Cancer Treatment. Biomed J Sci & Tech Res 47(3)-2022. BJSTR. MS.ID.007510.
4. Schneider MA, Heeb L, Beffinger MM, Pantelyushin S, Linecker M, Roth L, Lehmann K, Ungethüm U, Kobold S, Graf R, van den Broek M, Vom Berg J, Gupta A, Clavien PA. Attenuation of peripheral serotonin inhibits tumor growth and enhances immune checkpoint blockade therapy in murine tumor models. Sci Transl Med. 2021 Sep 15;13(611):eabc8188. doi: 10.1126/scitranslmed.abc8188. Epub 2021 Sep 15. PMID: 34524861.
5. Kofod J, Elfving B, Nielsen EH, Mors O, Köhler-Forsberg O. Depression and inflammation: Correlation between changes in inflammatory markers with antidepressant response and long-term prognosis. Eur Neuropsychopharmacol. 2022 Jan;54:116-125. doi: 10.1016/j.euroneuro.2021.09.006. Epub 2021 Sep 29. PMID: 34598835.
6. Liu FY, Cai J, Wang C, Ruan W, Guan GP, Pan HZ, Li JR, Qian C, Chen JS, Wang L, Chen G. Fluoxetine attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage: a possible role for the regulation of TLR4/MyD88/NF-κB signaling pathway. J Neuroinflammation. 2018 Dec 20;15(1):347. doi: 10.1186/s12974-018-1388-x. PMID: 30572907; PMCID: PMC6302437.
7. Hosomi S, Koyama Y, Watabe T, Ohnishi M, Ogura H, Yamashita T, Shimazu T. Myeloid-Derived Suppressor Cells Infiltrate the Brain and Suppress Neuroinflammation in a Mouse Model of Focal Traumatic Brain Injury. Neuroscience. 2019 May 15;406:457-466. doi: 10.1016/j.neuroscience.2019.03.015. Epub 2019 Mar 14. PMID: 30880103.
8. Saiwai H, Kumamaru H, Ohkawa Y, Kubota K, Kobayakawa K, Yamada H, Yokomizo T, Iwamoto Y, Okada S. Ly6C+ Ly6G- Myeloid-derived suppressor cells play a critical role in the resolution of acute inflammation and the subsequent tissue repair process after spinal cord injury. J Neurochem. 2013 Apr;125(1):74-88. doi: 10.1111/jnc.12135. Epub 2013 Jan 15. PMID: 23278273.

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Overview:

The review manuscript entitled “Traumatic Brain Injury and Cancer: The Intersection of Inflammation and T-Cell Exhaustion” by Zhukova et al seeks to establish a connection between Traumatic Brain Injury (TBI) and cancer, primarily focusing on the shared mechanisms of T-cell exhaustion and inflammation. While the subject of neuroimmune interactions is pertinent and potentially valuable, the manuscript is hindered by significant conceptual issues. These include fundamental errors in its conceptual framework, inconsistent definitions, an insufficiently substantiated rationale for drawing parallels between TBI and cancer, and a critical disconnect between the presented evidence and the clinical recommendations suggested.

General impression:

The manuscript attempts to highlight similarities in the underlying mechanistic pathways of TBI and cancer, specifically through the lens of inflammation and T-cell exhaustion. However, the approach lacks clarity and cohesion, with contradictory definitions that undermine the intended comparison. Additionally, the rationale for juxtaposing these two conditions is not robustly presented, which further detracts from the manuscript’s overall impact.

Section by section commentaries

In the following paragraphs, I will provide more detailed commentary on each section of the manuscript, outlining my impressions and concerns regarding the structure, conceptual accuracy, and coherence of the arguments presented.

Title and abstract:

The current title of the manuscript is problematic in several ways. It appears to suggest a causal relationship between traumatic brain injury (TBI) and cancer, rather than accurately reflecting the shared mechanisms of inflammation and T cell exhaustion present in both conditions. Specifically, the use of the word "Intersection" can be interpreted as indicating a clinical overlap or comorbidity (e.g., "Does TBI increase cancer risk?"), while the manuscript itself focuses on parallel mechanistic pathways rather than direct causality.

Additionally, the title does not reference sympathetic innervation, an element that is integral to the model proposed by the authors. This omission detracts from the clarity and relevance of the title, failing to communicate the mechanistic core of the paper. To better capture the central hypothesis, it is recommended that the title be revised to something more precise, such as “Neuroimmune dysregulation underlies the pathogenesis of brain injury and cancer.” Furthermore, the authors should provide a justification for associating traumatic brain injury and cancer within the context of their manuscript.

The abstract, as currently written, is insufficient in guiding the reader and fails to establish a strong conceptual framework for the manuscript. Instead of immediately introducing the neuroimmune dysregulation hypothesis—which is central to the discussion—it focuses on the "distinct nature" of traumatic brain injury (TBI) and cancer. This approach does not effectively communicate the shared mechanistic pathways that underpin both conditions.

A more compelling abstract should explicitly state that neuroimmune mechanisms are the driving force behind the pathology in both TBI and cancer. By doing so, the abstract would set a clearer foundation for the subsequent discussion of therapeutic strategies relevant to both disease processes. Merely listing topics, without connecting them through an overarching hypothesis, weakens the impact and coherence of the abstract, and indeed, of the entire manuscript.

In sum, the title fails to communicate the manuscript’s core mechanistic focus, and the abstract suffers from poor structure and lacks a clear, guiding hypothesis, which is necessary to orient the reader and define the scope of the work.

Conceptual fundations:

The manuscript's introduction opens with a definition of inflammation as a "pathological process," which stands in direct contradiction to basic physiological principles. Inflammation, by its nature, is a fundamental defensive mechanism essential for maintaining tissue homeostasis and responding to injury or infection. Mischaracterizing it as solely pathological undermines the conceptual accuracy of the discussion and confuses the reader regarding the role of inflammation in disease.

Furthermore, the rationale behind comparing traumatic brain injury (TBI) and cancer is inadequately developed and largely circumstantial. The text does not clearly articulate why examining these two conditions together provides unique insights, especially when other chronic inflammatory diseases are also mentioned. Without a compelling justification, the comparison lacks depth and specificity, failing to distinguish this pairing from broader discussions of chronic inflammation.

The manuscript also notes that T-cell exhaustion is a phenomenon observed across many chronic diseases. However, it does not establish a robust argumentative line that meaningfully connects tumor biology and neurotrauma beyond superficial mechanistic similarities. As a result, the premise of comparing TBI and cancer appears forced and arbitrary, rather than being based on well-founded scientific reasoning.

Immune checkpoints:

In this section, the manuscript’s internal logic becomes problematic. The authors review the role of the PD-1/PD-L1 axis and, citing Chen Q et al., explicitly acknowledge that, within the context of traumatic brain injury (TBI), the PD-L1 pathway serves a protective function. They further note that blockade of this pathway exacerbates cerebral edema and neuroinflammation.

Despite this critical admission, the manuscript continues to advocate for the application of cancer-like therapies—specifically checkpoint inhibitors, which are standard treatments in oncology—for TBI. This approach reveals a logical inconsistency: it is not reasonable to propose checkpoint inhibition for acutely injured brain tissue without first addressing the evidence that such interventions may worsen clinical outcomes or even prove lethal. The manuscript presents clear evidence of this risk, yet does not reconcile it with its overarching thesis, thereby undermining the coherence and safety of its proposed therapeutic strategies.

The Sympathetic Nervous System in Immune Regulation:

The discussion of the sympathetic nervous system (SNS) in the manuscript stands out as one of its most scientifically robust elements, specifically regarding the regulation of immune exhaustion. However, the effectiveness of this section is diminished by the absence of an introduction to the "neuroimmune axis" concept in both the title and the introduction. As a result, the section appears disconnected from the central narrative.

If the SNS serves as the principal mechanism linking traumatic brain injury (TBI) and cancer, the manuscript's current framing—as a straightforward comparison of inflammation—does not adequately reflect this focus. Instead, the content would be more appropriately situated within a review centered on neuroimmune dysautonomia, emphasizing the centrality of the SNS in uniting the pathophysiology of both conditions.

Interaction between Local and Systemic Inflammation:

Section 5 exhibits a notable lack of definitional congruence. The authors describe inflammation as a "physiological reaction... necessary for pathogen elimination," which directly contradicts the definition provided in the Introduction, where inflammation is characterized as a "pathological process." This inconsistency in fundamental concepts leads to reader confusion and highlights the absence of rigorous editorial review.

Furthermore, the structure of Section 5 is overly simplistic. The subsections addressing Cancer (5.1) and Traumatic Brain Injury (TBI) (5.2) are presented in parallel, but without meaningful synthesis. The text fails to offer a deep analysis of whether cytokine profiles or MDSC (Myeloid-Derived Suppressor Cells) kinetics are functionally homologous between these two conditions. Instead, the material is delivered as two juxtaposed summaries rather than as a critical and integrated comparative analysis.

Discussion (Conclusions):

The conclusions of the manuscript underscore and consolidate the earlier shortcomings identified throughout the text. The authors again propose the development of "combination therapeutic strategies based on immune response modulation." However, this recommendation is problematic given the evidence discussed in Section 3, which highlights the risk of cerebral edema associated with PD-L1 blockade. This key safety concern is not sufficiently addressed, indicating a lack of grounding in the overall therapeutic suggestion.

Moreover, the disconnect between the literature review and the practical clinical application becomes apparent. The manuscript fails to resolve whether a causal relationship exists between traumatic brain injury (TBI) and cancer. Instead of providing clarity or a meaningful translational pathway, the text concludes with a phenomenological comparison that does not offer concrete utility for clinical practice or future research directions.

Comments on the Quality of English Language

The manuscript suffers from a lack of narrative cohesion. Rather than a synthesized comparative analysis, the text often reads as two separate literature reviews (one on TBI, one on Cancer) placed side-by-side without sufficient integration. The flow is disjointed, particularly in Section 5, where the comparison is superficial. Technical writing is compromised by imprecise definitions (e.g., the inflammation definition in the Introduction) and contradictory statements regarding therapeutic safety. Finally, the English usage requires editing to correct unidiomatic phrasing (e.g., "paying close attention") that hinders readability.

Author Response

Dear Reviewer,

Thank you very much for taking the time to review and a deep analytical perspective in evaluating this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

Below are the answers and clarifications to your remarks and comments.

Comments 1: The review manuscript entitled “Traumatic Brain Injury and Cancer: The Intersection of Inflammation and T-Cell Exhaustion” by Zhukova et al seeks to establish a connection between Traumatic Brain Injury (TBI) and cancer, primarily focusing on the shared mechanisms of T-cell exhaustion and inflammation. While the subject of neuroimmune interactions is pertinent and potentially valuable, the manuscript is hindered by significant conceptual issues. These include fundamental errors in its conceptual framework, inconsistent definitions, an insufficiently substantiated rationale for drawing parallels between TBI and cancer, and a critical disconnect between the presented evidence and the clinical recommendations suggested.

The manuscript attempts to highlight similarities in the underlying mechanistic pathways of TBI and cancer, specifically through the lens of inflammation and T-cell exhaustion. However, the approach lacks clarity and cohesion, with contradictory definitions that undermine the intended comparison. Additionally, the rationale for juxtaposing these two conditions is not robustly presented, which further detracts from the manuscript’s overall impact.

Response 1: Thank you for your comment. The manuscript aimed to compare and identify differences between TBI and cancer in the following areas: immune cell response, T-cell exhaustion, systemic and local inflammation, and approaches to correcting exhaustion and inflammation. We did not aim to establish a link between the development of TBI and cancer. To clarify our concept, we have changed the title and abstract of the article.

The choice of these pathologies for comparison was based on our experience. Previously, our group conducted research in the field of cancer and T-cell exhaustion, including its treatment. Currently, our interests have expanded, and we have begun research in the field of neuroimmunology. This became a point of contact and prompted us to conduct a comparative analysis of the two pathologies, despite the lack of direct common pathophysiological mechanisms between them.

To make our concept clearer, we revised the manuscript title and the abstract.

Comments 2: The current title of the manuscript is problematic in several ways. It appears to suggest a causal relationship between traumatic brain injury (TBI) and cancer, rather than accurately reflecting the shared mechanisms of inflammation and T cell exhaustion present in both conditions. Specifically, the use of the word "Intersection" can be interpreted as indicating a clinical overlap or comorbidity (e.g., "Does TBI increase cancer risk?"), while the manuscript itself focuses on parallel mechanistic pathways rather than direct causality.

Response 2: Thank you for your suggestion. We changed the title to "Neuroimmune Mechanisms in Traumatic Brain Injury and Cancer: Parallel Courses or Existence in Different Orbits"

Comments 3: Additionally, the title does not reference sympathetic innervation, an element that is integral to the model proposed by the authors. This omission detracts from the clarity and relevance of the title, failing to communicate the mechanistic core of the paper. To better capture the central hypothesis, it is recommended that the title be revised to something more precise, such as “Neuroimmune dysregulation underlies the pathogenesis of brain injury and cancer.” Furthermore, the authors should provide a justification for associating traumatic brain injury and cancer within the context of their manuscript.

Response 3: Thank you for your remark. We upgraded the title to "Neuroimmune Mechanisms in Traumatic Brain Injury and Cancer: Parallel Courses or Existence in Different Orbits"

Comments 4: The abstract, as currently written, is insufficient in guiding the reader and fails to establish a strong conceptual framework for the manuscript. Instead of immediately introducing the neuroimmune dysregulation hypothesis—which is central to the discussion—it focuses on the "distinct nature" of traumatic brain injury (TBI) and cancer. This approach does not effectively communicate the shared mechanistic pathways that underpin both conditions.

Response 4: Thank you for your comment. We revised the abstract to make it clearer.

Comments 5: A more compelling abstract should explicitly state that neuroimmune mechanisms are the driving force behind the pathology in both TBI and cancer. By doing so, the abstract would set a clearer foundation for the subsequent discussion of therapeutic strategies relevant to both disease processes. Merely listing topics, without connecting them through an overarching hypothesis, weakens the impact and coherence of the abstract, and indeed, of the entire manuscript.

Response 5: Thank you for your comment. We did not aim to establish a definitive causal relationship between TBI and cancer. We adjusted the abstract to make the review's objective clearer and changed the title to highlight the key role of neuroimmune mechanisms in cancer and TBI.

Comments 6: In sum, the title fails to communicate the manuscript’s core mechanistic focus, and the abstract suffers from poor structure and lacks a clear, guiding hypothesis, which is necessary to orient the reader and define the scope of the work.

Response 6: We are grateful for your comment. We edited the abstract to make it more logical and clear.

Comments 7: The manuscript's introduction opens with a definition of inflammation as a "pathological process," which stands in direct contradiction to basic physiological principles. Inflammation, by its nature, is a fundamental defensive mechanism essential for maintaining tissue homeostasis and responding to injury or infection. Mischaracterizing it as solely pathological undermines the conceptual accuracy of the discussion and confuses the reader regarding the role of inflammation in disease.

Response 7: Thank you for your valuable comment. We accepted it and revised the first paragraph, lines 26-30.

Comments 8: Furthermore, the rationale behind comparing traumatic brain injury (TBI) and cancer is inadequately developed and largely circumstantial. The text does not clearly articulate why examining these two conditions together provides unique insights, especially when other chronic inflammatory diseases are also mentioned. Without a compelling justification, the comparison lacks depth and specificity, failing to distinguish this pairing from broader discussions of chronic inflammation.

Response 8: Thank you for these remarks. The aim of our study was to compare TBI and cancer based on the following parameters: immune cell response, T-cell exhaustion, systemic and local inflammation, and approaches to correcting exhaustion and inflammation. However, our analysis failed to identify any strong commonalities between TBI and cancer. To clarify our concept, we have revised the abstract. The choice of these pathologies for comparison is based on our previous research experience and the research interests of our group.

Comments 9: The manuscript also notes that T-cell exhaustion is a phenomenon observed across many chronic diseases. However, it does not establish a robust argumentative line that meaningfully connects tumor biology and neurotrauma beyond superficial mechanistic similarities. As a result, the premise of comparing TBI and cancer appears forced and arbitrary, rather than being based on well-founded scientific reasoning.

Response 9: Thank you for your comment. The choice of these pathologies for comparison is based on our previous research experience and the interests of our research group.

Comments 10: In this section, the manuscript’s internal logic becomes problematic. The authors review the role of the PD-1/PD-L1 axis and, citing Chen Q et al., explicitly acknowledge that, within the context of traumatic brain injury (TBI), the PD-L1 pathway serves a protective function. They further note that blockade of this pathway exacerbates cerebral edema and neuroinflammation.

Response 10: Thank you for your comment. We have updated section 6.2, line 455, and the discussion to clarify any misinterpretation.

Comments 11: Despite this critical admission, the manuscript continues to advocate for the application of cancer-like therapies—specifically checkpoint inhibitors, which are standard treatments in oncology—for TBI. This approach reveals a logical inconsistency: it is not reasonable to propose checkpoint inhibition for acutely injured brain tissue without first addressing the evidence that such interventions may worsen clinical outcomes or even prove lethal. The manuscript presents clear evidence of this risk, yet does not reconcile it with its overarching thesis, thereby undermining the coherence and safety of its proposed therapeutic strategies.

Response 11: Thank you for your comment. We revised the discussion to include information about the similarities and differences in the mechanisms of inflammation, exhaustion, and immune cell response to address any inconsistencies.

Comments 12: The discussion of the sympathetic nervous system (SNS) in the manuscript stands out as one of its most scientifically robust elements, specifically regarding the regulation of immune exhaustion. However, the effectiveness of this section is diminished by the absence of an introduction to the "neuroimmune axis" concept in both the title and the introduction. As a result, the section appears disconnected from the central narrative.

Response 12: Thank you for your constructive comment. We added a Figure 1 showing the influence of the sympathetic nervous system and the hypothalamic-pituitary axis on immune function in TBI.

Comments 13: If the SNS serves as the principal mechanism linking traumatic brain injury (TBI) and cancer, the manuscript's current framing—as a straightforward comparison of inflammation—does not adequately reflect this focus. Instead, the content would be more appropriately situated within a review centered on neuroimmune dysautonomia, emphasizing the centrality of the SNS in uniting the pathophysiology of both conditions.

Response 13: Thank you for your constructive feedback. We believe that the SNS is only one mechanism, along with inflammation. We do not rule out the possibility that the SNS is a link between TBI and cancer, but during our review, we found no convincing evidence to support this suggestion.

Comments 14: Section 5 exhibits a notable lack of definitional congruence. The authors describe inflammation as a "physiological reaction... necessary for pathogen elimination," which directly contradicts the definition provided in the Introduction, where inflammation is characterized as a "pathological process." This inconsistency in fundamental concepts leads to reader confusion and highlights the absence of rigorous editorial review.

Response 14: Thank you for your valuable remarks. We changed the introduction to include that inflammation is a fundamental process to eliminate the inconsistency that exists in section 5.

Comments 15: Furthermore, the structure of Section 5 is overly simplistic. The subsections addressing Cancer (5.1) and Traumatic Brain Injury (TBI) (5.2) are presented in parallel, but without meaningful synthesis. The text fails to offer a deep analysis of whether cytokine profiles or MDSC (Myeloid-Derived Suppressor Cells) kinetics are functionally homologous between these two conditions. Instead, the material is delivered as two juxtaposed summaries rather than as a critical and integrated comparative analysis.

Response 15: Thank you for your comment. Data on MDSC kinetics in TBI are too limited. Therefore, a thorough analysis of the relationship between TBI and cancer in these areas is difficult, and the identified gaps require further study. However, we updated the information on the role of myeloid-derived suppressor cells in TBI in the part 2.1, lines 133-158.

Comments 16: The conclusions of the manuscript underscore and consolidate the earlier shortcomings identified throughout the text. The authors again propose the development of "combination therapeutic strategies based on immune response modulation." However, this recommendation is problematic given the evidence discussed in Section 3, which highlights the risk of cerebral edema associated with PD-L1 blockade. This key safety concern is not sufficiently addressed, indicating a lack of grounding in the overall therapeutic suggestion.

Response 16: Thank you for your comment. We revised the discussion to better suit the purpose of the manuscript.

Comments 17: Moreover, the disconnect between the literature review and the practical clinical application becomes apparent. The manuscript fails to resolve whether a causal relationship exists between traumatic brain injury (TBI) and cancer. Instead of providing clarity or a meaningful translational pathway, the text concludes with a phenomenological comparison that does not offer concrete utility for clinical practice or future research directions.

Response 17: We sincerely appreciate your feedback. The purpose of this review was not to establish a causal relationship between TBI and cancer. We believe this is a topic for a separate review. We have updated the "Discussion" section to highlight the gaps in TBI research. 

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

Traumatic Brain Injury and Cancer : The Intersection of Inflammation and T-Cell Exhaustion

 

Report comment

Biomedicines-4003295

This interesting study aims to synthesize the available data on the links between local and systemic inflammation, with a particular focus on inflammation in traumatic brain injury (TBI). It also seeks to compare the current state of knowledge on T-cell exhaustion in TBI with that in cancer, where this phenomenon is better characterized. I still have some suggestions to incorporate, as indicated below.

Introduction

Lines 30-31 : The transition between the general discussion on chronic inflammation and the introduction of T cell exhaustion could be a little smoother.

Lines 43-45: Add a sentence emphasizing that peripheral immune function (including exhaustion) can influence or be influenced by neuroinflammation.

Lines 53-55: Ask an implicit or explicit question in the introduction (Are the mechanisms of exhaustion observed in cancer also active/relevant in the unique context of TBI?)

2. The Immune System in Traumatic Brain Injury

Lines 81-91:

The text mentions immunosuppression and mechanisms (MDSCs, DAMPs). You should connect these mechanisms to T cell exhaustion.

Explain how these elements (DAMPs, MDSCs) contribute to immune dysfunction in TBI.

Lignes 71-74 :

Vous pourriez ajouter que cette variabilité complique l'identification d'une signature immunitaire systémique persistante, ce qui justifie d'examiner les mécanismes sous-jacents comme l'épuisement.

3-Immune Checkpoints

How chronic inflammation or cellular stress activates these checkpoints and why this differs depending on the context.

Some sentences are very long and detail several experimental points simultaneously.

Information on cytokines and signaling pathways could be summarized in a table or diagram showing the interactions between PD-1/PD-L1, LAG-3, and T-cell exhaustion.

4. The Sympathetic Nervous System in Immune Regulation

This section is dense and combines information on basic physiology, immune regulation, and the impact on cancer/TBI. It would be beneficial to divide it into subheadings (e.g., SNS and immune regulation, SNS and cancer, SNS and TBI) to improve readability.

The mechanisms described (Treg activation, checkpoint expression, immune cell mobilization) are interesting but presented in a very textual manner. Adding a diagram or summary table could clarify the relationship between SNS, immune checkpoints, and pathological effects in cancer and TBI.

5. Interaction between Local and Systemic Inflammation

It would be useful to briefly highlight the conceptual link, for example how the regulation of cytokines and immune cells can influence tumor progression or neuroinflammation.

Line 684 remove marker

 

Author Response

Dear Reviewer,

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in track changes in the re-submitted files.

Below are the answers and clarifications to your questions and comments.

Comments 1: Lines 30-31: The transition between the general discussion on chronic inflammation and the introduction of T cell exhaustion could be a little smoother.

Response 1: Thank you for the comment. We added the “In addition, prolonged antigenic stimulation that occurs during chronic inflammation, humoral and cellular inflammatory components, creates conditions for T-cell exhaustion [Fang L, Liu K, Liu C, Wang X, 2022; Mu W, Patankar V, Kitchen S, 2024]” to make the transition from inflammation to exhaustion smoother, lines 36-38.

References:

1. Fang L, Liu K, Liu C, Wang X, Ma W, Xu W, Wu J, Sun C. Tumor accomplice: T cell exhaustion induced by chronic inflammation. Front Immunol. 2022 Sep 2;13:979116. doi: 10.3389/fimmu.2022.979116. PMID: 36119037; PMCID: PMC9479340.
2. Mu W, Patankar V, Kitchen S, Zhen A. Examining Chronic Inflammation, Immune Metabolism, and T Cell Dysfunction in HIV Infection. Viruses. 2024 Jan 31;16(2):219. doi: 10.3390/v16020219. PMID: 38399994; PMCID: PMC10893210.

Comments 2: Lines 43-45: Add a sentence emphasizing that peripheral immune function (including exhaustion) can influence or be influenced by neuroinflammation.

Response 2: Thank you for the suggestion. We corrected lines to "Given the existing link between the immune system and the central nervous system, the development of T-cell exhaustion in neuroinflammation is of particular interest." to highlight the possible link between neuroinflammation and exhaustion. We added the text in lines 50-51.

Comments 3: Lines 53-55: Ask an implicit or explicit question in the introduction (Are the mechanisms of exhaustion observed in cancer also active/relevant in the unique context of TBI?)

Response 3: Thank you for the remarks. We added “However, this requires an understanding of the underlying mechanisms of traumatic brain injury. In particular, it remains unclear whether the mechanisms of T-cell exhaustion in cancer and TBI are similar or unique to each pathology”, lines 60-63.

Comments 4: Lines 81-91: The text mentions immunosuppression and mechanisms (MDSCs, DAMPs). You should connect these mechanisms to T cell exhaustion. Explain how these elements (DAMPs, MDSCs) contribute to immune dysfunction in TBI.

Response 4: Thank you for your comments. The initiating moment in the development of immune dysfunction following TBI is believed to be the release of DAMPs such as glial protein S100B, HMGB1, and ATP [Sun B, Zhang J, Li Z, Wang J, 2025]. In response, microglia produce several cytokines, including IL-1β and IL-6, which enter the bloodstream and promote the recruitment of immune cells, including MDSCs, from the periphery to the brain [Salminen A, Kaarniranta K, Kauppinen A. 2018; Bouras M, Asehnoune K, Roquilly A. 2022]. Additionally, HMGB1 promotes MDSC expansion via the receptor for advanced glycation end-products [Liesz A, Dalpke A, Mracsko E, Antoine DJ, 2015]. It is believed that the immunosuppressive activity of MDSCs in TBI is associated with:

- altered L-arginine metabolism and competition between MDSCs and T-cells

- production of reactive oxygen and nitrogen species, which leads to nitration of TCR and CD8 receptor and disrupts MHC-mediated T-cell stimulation [Cheng L, Xu J, Chai Y, Wang C, 2017]. These mechanisms are largely similar to the processes occurring in cancer.

MDSC subpopulations differ in their functional activity. G-MDSCs more actively produce reactive oxygen species, while M-MDSCs produce more nitric oxide. By expressing more iNOS, M-MDSCs more actively suppress immune cell function by inhibiting T-cell JAK3 and STAT5 [Nagaraj S, Gabrilovich DI. 2012].

We added this information in the part 2.1 «The Immune System in Traumatic Brain Injury», lines 127-138.

References:

1. Sun B, Zhang J, Li Z, Wang J, Zhao C, Xu X. Role of damage-associated molecular patterns in the pathogenesis and therapeutics of traumatic brain injury. Burns Trauma. 2025 Jul 13;13:tkaf043. doi: 10.1093/burnst/tkaf043. PMID: 41103638; PMCID: PMC12526888.
2. Cheng L, Xu J, Chai Y, Wang C, Han P. Dynamic changes in trauma-induced myeloid-derived suppressor cells after polytrauma are associated with an increased susceptibility to infection. Int J Clin Exp Pathol. 2017 Nov 1;10(11):11063-11068. PMID: 31966453; PMCID: PMC6965885.
3. Nagaraj S, Gabrilovich DI. Regulation of suppressive function of myeloid-derived suppressor cells by CD4+ T cells. Semin Cancer Biol. 2012 Aug;22(4):282-8. doi: 10.1016/j.semcancer.2012.01.010. Epub 2012 Jan 31. PMID: 22313876; PMCID: PMC3349790.

Comments 5: Lignes 71-74 :Vous pourriez ajouter que cette variabilité complique l'identification d'une signature immunitaire systémique persistante, ce qui justifie d'examiner les mécanismes sous-jacents comme l'épuisement.

Response 5: Thank you for the comment. We added "“Such ambiguous data on the systemic immune response in traumatic brain injury make it difficult to study underlying mechanisms such as exhaustion." to the text, lines 90-91.

Comments 6: How chronic inflammation or cellular stress activates these checkpoints and why this differs depending on the context. Some sentences are very long and detail several experimental points simultaneously. Information on cytokines and signaling pathways could be summarized in a table or diagram showing the interactions between PD-1/PD-L1, LAG-3, and T-cell exhaustion.

Response 6: Thank you for this valuable comment. This issue is indeed relevant. To date, we have found no information on context-dependent differences in immune checkpoint activation. This is likely due to the commonality of fundamental processes occurring in various pathologies, such as cancer and TBI. However, we have supplemented Figure 1 and expanded our information on the cytokines involved in cancer development and TBI-related changes. Regarding the interactions between signaling pathways and immune checkpoints, given the large number of signaling pathways involved in exhaustion and the large number of studies and reviews devoted to their investigation, we believe this information would be redundant in the context of our review.

Comments 7: This section is dense and combines information on basic physiology, immune regulation, and the impact on cancer/TBI. It would be beneficial to divide it into subheadings (e.g., SNS and immune regulation, SNS and cancer, SNS and TBI) to improve readability.

Response 7: Thank you for the comments. We divided the part 4 "The Sympathetic Nervous System in Immune Regulation" into two subheadings. 

Comments 8: The mechanisms described (Treg activation, checkpoint expression, immune cell mobilization) are interesting but presented in a very textual manner. Adding a diagram or summary table could clarify the relationship between SNS, immune checkpoints, and pathological effects in cancer and TBI.

Response 8: Thank you for your suggestion. We added Figure 1 showing the relationship between immunosuppression and TBI and modified Figure 2 to be more detailed.

Comments 9: It would be useful to briefly highlight the conceptual link, for example how the regulation of cytokines and immune cells can influence tumor progression or neuroinflammation.

Response 9: Thank you for the suggestion. We agree that such a comparison would be valuable. However, given the large volume of information involved, we believe this issue should be addressed in a separate article. We revised a figure (Figure 2) showing the key signaling molecules involved in cancer development and post-TBI damage.

Comments 10: Line 684 remove marker

Response 10: Thank you for your comment. We removed the marker.

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

The review focuses on a very relevant subject of systemic inflammation and T-cell exhaustion in the context of TBI and cancer, paralleling the mechanisms involved in both disorders and identifying methods involved in the correction of neuroinflammation.

The structure, including the relevance of immune system and its regulation in TBI and cancer and focusing also in the methods to reduce inflammation and reversal of T-cell exhaustion, is of relevance to the field.

However there are several concerns that I think should be addressed.

1 - When comparing TBI with cancer, which type of cancer is being addressed? All types? Or is there a type of cancer that is more comparable to TBI?

2 -  There is a section on the immune system in traumatic brain injury. Mayb there should also be a section of immune system in cancer.

3 – In what refers to the immune cells involved in responses to TBI and cancer, the paper addresses mostly MDSCs, neutrophils, CD4 and CD8 T cells but there are also other cells of the immune system that were poorly mentioned – such as Tregs or not even mentioned – such as the innate-like T cells gd T cells and NKT cells. And these should be included in the paper.

Figure 1 summarises the information on the Key players in the development of local inflammation in cancer and traumatic brain injury. This figure should include the several immune cells populations involved in this process and also all the cytokines produced by each cells. Those presented are very little informative and there are more cytokines than tose shown in the scheme. For example IFNg is very relevant for these processes and it is not mentioned.

 

Minor: the first sentence of the introduction is the following: 

"Inflammation is a fundamental pathological process designed to localize the pathological process, promote its rapid resolution, and restore damaged tissues [1]". Lines 23 and 24. This sentence used the word pathological twice. It should be re-written as well as other sentences that might include these types of mistakes. 

Author Response

Dear Reviewer,

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in track changes in the re-submitted files.

Below are the answers and clarifications to your questions and comments.

Comments 1: When comparing TBI with cancer, which type of cancer is being addressed? All types? Or is there a type of cancer that is more comparable to TBI?

Response 1: Thank you for your question. In this review, we attempted to draw parallels between two seemingly fundamentally different pathologies—cancer and TBI. In this review, we did not focus on any one type of cancer, but rather emphasized common mechanisms common to most types of cancer.

Comments 2: There is a section on the immune system in traumatic brain injury. Mayb there should also be a section of immune system in cancer.

Response 2: Thank you for your valuable comment. We separated a subsection 2.2. "The Immune System in Cancer". 

Comments 3: In what refers to the immune cells involved in responses to TBI and cancer, the paper addresses mostly MDSCs, neutrophils, CD4 and CD8 T cells but there are also other cells of the immune system that were poorly mentioned – such as Tregs or not even mentioned – such as the innate-like T cells gd T cells and NKT cells. And these should be included in the paper.

Response 3: Thank you for the suggestion. We added information about other immune cells involved in TBI in subsection 2.1. "The Immune System in Traumatic Brain Injury", lines 100-124.

Comments 4: Figure 1 summarises the information on the Key players in the development of local inflammation in cancer and traumatic brain injury. This figure should include the several immune cells populations involved in this process and also all the cytokines produced by each cells. Those presented are very little informative and there are more cytokines than tose shown in the scheme. For example IFNg is very relevant for these processes and it is not mentioned.

Response 4: We agree with the comment. We have updated Figure 1 (it became Figure 2) to include more information about the cytokines, signaling pathways, and cells involved in the development of cancer and TBI injury.

Comments 5: Minor: the first sentence of the introduction is the following: 

"Inflammation is a fundamental pathological process designed to localize the pathological process, promote its rapid resolution, and restore damaged tissues [1]". Lines 23 and 24. This sentence used the word pathological twice. It should be re-written as well as other sentences that might include these types of mistakes. 

Response 5: Thanks for the comment. We've changed the first paragraph to "Inflammation is a fundamental process, serving as the body's first line of defense against various damaging factors. It's important to note that inflammation has a dual nature. While acute inflammation is aimed at localizing the pathological process, its rapid resolution, and the restoration of damaged tissue, chronic inflammation is an integral component of several diseases [1]", lines 26-30.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I acknowledge the authors' efforts to address the specific technical inaccuracies pointed out in my previous review. The corrections regarding the physiological definition of inflammation and the adjustment of the title to remove the implication of direct causality are noted and appreciated.

However, the primary structural and conceptual objection raised in the first round of review remains unresolved. My previous recommendation specifically urged a restructuring of the manuscript around the "Neuroimmune/SNS Axis" to provide a unified mechanistic narrative. In your response (specifically Response 17), you stated that establishing such a causal or mechanistic relationship is "a topic for a separate review" and that the purpose of this manuscript is not to establish causality.

Regrettably, this decision limits the manuscript to a "parallel" structure—as admitted by the new title ("Parallel Courses")—where TBI and Cancer are discussed in juxtaposition rather than in synthesis. Without a unifying mechanistic thread (such as the SNS dysautonomia previously suggested), the review functions as two separate summaries placed side-by-side.

Specific Concerns:

1. Lack of Synthesis: Section 5 remains divided into distinct subsections (5.1 for Cancer, 5.2 for TBI) without a deep integrated analysis. A high-quality review should create new knowledge by synthesizing connections, not merely listing similarities.

2. Therapeutic Inconsistency: While cautionary language regarding PD-L1 blockade in TBI has been added, the underlying logical issue persists. Structuring a review around shared therapeutic targets (checkpoints) loses translational value when the evidence suggests that the same target requires opposite interventions (activation vs. inhibition) in the two conditions.

3. Missed Opportunity: By declining to pivot the review towards the neuroimmune/SNS axis, the manuscript misses the opportunity to offer a novel perspective and remains a descriptive text with limited utility for clinical guidance or future research design.

Conclusion: While the manuscript is now technically more accurate than the previous version, it still lacks the narrative cohesion and mechanistic depth required for publication. Corrections look like "cosmetic" elements, rather than derived from a genuine process of critical thinking.

Comments on the Quality of English Language

Although the grammatical accuracy has slightly improved, the manuscript continues to suffer from unidiomatic phrasing and stiff sentence structures (e.g., constructions like "Particular attention is paid to..."; the Abstract remain passive and clunky). This lack of linguistic fluidity hinders readability and exacerbates the disjointed feeling of the text. The manuscript would require extensive professional editing to reach the standard expected for publication, but this is secondary to the major structural flaws previously noted.

Author Response

We greatly appreciate your careful evaluation of our manuscript. Please find the corresponding revisions/corrections highlighted in the re-submitted files.

Comments 1: However, the primary structural and conceptual objection raised in the first round of review remains unresolved. My previous recommendation specifically urged a restructuring of the manuscript around the "Neuroimmune/SNS Axis" to provide a unified mechanistic narrative. In your response (specifically Response 17), you stated that establishing such a causal or mechanistic relationship is "a topic for a separate review" and that the purpose of this manuscript is not to establish causality.

Regrettably, this decision limits the manuscript to a "parallel" structure—as admitted by the new title ("Parallel Courses")—where TBI and Cancer are discussed in juxtaposition rather than in synthesis. Without a unifying mechanistic thread (such as the SNS dysautonomia previously suggested), the review functions as two separate summaries placed side-by-side.

Response 1: Thank you for your comment. We deeply appreciate your attention to the role of neuroimmune interactions/the sympathetic nervous system, as well as your suggestion regarding a possible conceptual reorganization of the manuscript. We share the view on the significance of this mechanism for understanding immune dysregulation.

At the same time, our chosen structure and presentation logic are a conscious decision, reflecting our scientific experience and conceptual intent. The primary goal of this work was a comparative analysis of cancer and TBI, not the construction of a single "mechanistic" model. In this context, the “parallel” structure of the manuscript reflects not the absence of a conceptual connection, but rather the desire to avoid excessive generalizations and speculative interpretations, especially given the varying degrees of study of the processes being analyzed.

We view parallel comparison as a tool for identifying differences, inconsistencies, and existing gaps in knowledge, particularly in TBI research. Attempting to combine cancer and TBI under a single mechanistic axis, such as dysautonomia of the nervous system, would not fully capture the specific characteristics of each pathology.

We acknowledge the significant role of neuroimmune interactions and the sympathetic nervous system and discuss them in the relevant sections. However, these mechanisms are considered one element of a complex, multicomponent system involved in the development of changes in TBI and cancer, rather than a single unifying concept.

Comments 2: Lack of Synthesis: Section 5 remains divided into distinct subsections (5.1 for Cancer, 5.2 for TBI) without a deep integrated analysis. A high-quality review should create new knowledge by synthesizing connections, not merely listing similarities.

Response 2: Thank you for your comment. We would like to emphasize that the purpose of this review was to compare two pathologies: cancer and TBI. It would be short-sighted to aim for the acquisition of new knowledge in a review article. We believe that new knowledge can only be generated through experimental or clinical research. The purpose of this manuscript is to systematize and summarize existing data, provide an understanding of the current state of the issue, and identify existing gaps in knowledge.

We also revised the structure of Section 5 to make it more consistent.

Comments 3: Therapeutic Inconsistency: While cautionary language regarding PD-L1 blockade in TBI has been added, the underlying logical issue persists. Structuring a review around shared therapeutic targets (checkpoints) loses translational value when the evidence suggests that the same target requires opposite interventions (activation vs. inhibition) in the two conditions.

Response 3: We would like to emphasize that the manuscript does not discuss PD-L1 blockade in TBI. In Section 6.2, line ..., it is stated that, although PD-1/PD-L1 blockers (antagonists) have proven effective in the treatment of cancer, PD-1/PD-L1 agonists are considered potential agents for the treatment of TBI.

We do not consider the "opposite intervention" a drawback. On the contrary, this apparent contradiction highlights the need for a more in-depth study of immune mechanisms in general, and immune checkpoints in particular, in various pathological processes. From a practical perspective, this highlights the importance of a personalized approach to the selection of therapeutic strategies, taking into account the characteristics of a specific pathology.

Comments 4: Missed Opportunity: By declining to pivot the review towards the neuroimmune/SNS axis, the manuscript misses the opportunity to offer a novel perspective and remains a descriptive text with limited utility for clinical guidance or future research design.

Response 4: Thank you for your comment. We wish to underscore that the purpose of this review article is to systematize and summarize existing information, not to create new knowledge or formulate clinical guidelines. From this perspective, the chosen structure allows us to present existing information while highlighting existing knowledge gaps.

It is important to note that our review covers a broad range of changes, including local and systemic inflammation, quantitative and functional variation in immune cells whose role has not been fully established, and other aspects. This broad approach is an advantage of this review article, allowing us to develop a more comprehensive understanding of the changes occurring without limiting the material to a description of the neuroimmune axis. It should also be noted that the limited amount of information on TBI does not allow for a full description of the neuroimmune axis, and attempts to artificially construct one could lead to speculative conclusions.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

For Figures 1 and 2, please ensure that two appropriate references are cited for each figure, if applicable. 

Author Response

Thank you very much for taking the time to review this manuscript. Please find the corresponding revisions/corrections highlighted in the re-submitted files.

Comments 1: For Figures 1 and 2, please ensure that two appropriate references are cited for each figure, if applicable. 

Response 1: Thank you for the comment. We have added references in the captions of Figure 1 and Figure 2.

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for the changes introduced that have contributed to valorize your manuscript. I have only minor questions which are a consequence of the recent changes to the paper. Since a larger section on The Immune System in Traumatic Brain Injury" was introduced with detailed description on several T cells, this should be mimicked in section 2.2 where the same cells should be described and not just MDSCs and DAMPs as previously. 

I also thank you for the updated figures that are more informative.

And I finally ask you to review some of the references introduced in the text that are still not introduced in the reference list.

 

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.

Below are the answers and clarifications to your questions and comments.

Comments 1: Since a larger section on The Immune System in Traumatic Brain Injury" was introduced with detailed description on several T cells, this should be mimicked in section 2.2 where the same cells should be described and not just MDSCs and DAMPs as previously. 

Response 1: Thank you for your remark. We added the information about G-MDSCs, M-MDSCs, NKT-, B-, and γδT-cells in cancer to Section 2.2, lines 158-186 and 202-208.

Comments 2: And I finally ask you to review some of the references introduced in the text that are still not introduced in the reference list.

Response 2: We corrected the reference list.

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

I can no longer review this article. This is the third round, and the authors remain reluctant to address my main concerns. They justify their obstinacy without constructing a convincing narrative that refutes my argument regarding the article's design. The manuscript has certainly improved, but it still lacks scholarly rigor. Nevertheless, since I find it readable and potentially useful as it stands, I recommend its acceptance with minor revisions. Please pay particular attention to narrative flow while working on the final publishable version.

Comments on the Quality of English Language

Although the grammatical accuracy has slightly improved, the manuscript continues to suffer from unidiomatic phrasing and stiff sentence structures (e.g., constructions like "Particular attention is paid to..."; the Abstract remain passive and clunky). This lack of linguistic fluidity hinders readability and exacerbates the disjointed feeling of the text. The manuscript would require extensive professional editing to reach the standard expected for publication, but this is secondary to the major structural flaws previously noted.