Exploration of the Dual Role of Dectin-1 in Tumor Development and Its Therapeutic Potential

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Review of Manuscript: The Dual Role of Dectin-1 in Tumor Biology

The primary question the research addresses is the dual role of Dectin-1, a C-type lectin receptor, in cancer biology. Specifically, it examines how Dectin-1 can exhibit both pro-tumor and anti-tumor activities depending on the tumor type and microenvironment.

The topic is relevant and original within the field of tumor immunology. Immunotherapy, particularly targeting immune checkpoint inhibitors, has been a major focus in cancer treatment. However, the role of the innate immune system and Pattern Recognition Receptors (PRRs) like Dectin-1 in cancer is a relatively new and emerging area of research.

It also highlights the intricate mechanisms through which Dectin-1 can either promote or inhibit tumor growth, depending on the context. This dual role is crucial for understanding how to potentially manipulate Dectin-1 signaling pathways for therapeutic purposes.

Methodology: The manuscript provides a detailed review of existing studies and mechanisms. However, including more specific experimental data or case studies would strengthen the arguments. If feasible, the authors could incorporate in vitro and in vivo studies to validate the dual role of Dectin-1. Also clinical aspect. Drug intervention .signal aspect eg, nfkb.

To improve the robustness of the conclusions, the authors should consider: Utilizing different tumor microenvironments to see how Dectin-1's role changes. Including controls with other PRRs to compare and contrast their roles in tumor biology, explaining how its activation can lead to either tumor suppression or promotion. The detailed discussion on the interaction between Dectin-1 and other membrane molecules, as well as the impact of the tumor microenvironment, supports the main question posed. 

Please add referencing to your Tabl1,2. Please improve English .

 

Comments on the Quality of English Language

please check parglarism 

Author Response

Comments from reviewer one:

Comments 1: The manuscript provides a detailed review of existing studies and mechanisms. 1. However, including more specific experimental data or case studies would strengthen the arguments. If feasible, the authors could incorporate in vitro and in vivo studies to validate the dual role of Dectin-1. Also clinical aspect. Drug intervention .signal aspect eg, nfkb.

Response:

Thank you for reviewing our manuscript! We have made revisions according to your constructive suggestions.

Please check line 141-151, line155-163. We have included more experimental data including certain in vitro and in vivo studies in these sections.

Please check line 169-198, 223-229, 233-236, 242-250. We have highlighted the experiment data in these sections.

 

Comments 2: To improve the robustness of the conclusions, the authors should consider: Utilizing different tumor microenvironments to see how Dectin-1's role changes. Including controls with other PRRs to compare and contrast their roles in tumor biology, explaining how its activation can lead to either tumor suppression or promotion. The detailed discussion on the interaction between Dectin-1 and other membrane molecules, as well as the impact of the tumor microenvironment, supports the main question posed. 

Response:

Thank you for your suggestions! We have revised the discussion part of the manuscript according to your constructive insights.

Please check line 333-342. This section illustrates the varying roles of Dectin-1 within different tumor microenvironments, highlighting its microenvironment-dependent functions in tumor biology and the resulting differences arising from its activation in various immune cell types.

Please check line 334-378. This section introduced Toll-like receptors as a point of comparison and discussed the differences in the roles of Dectin-1 and TLRs in tumor biology and the potential reasons for these differences. It further elucidated the distinctive characteristics of Dectin-1's function in the context of tumor biology.

Please check line 379-391. Currently, there is a limited amount of research examining the impact of Dectin-1 interactions with other membrane molecules on the tumor microenvironment and its subsequent outcomes. This section explored this topic in light of the existing literature.

 

Comments 3: Please add referencing to your Tabl1,2. Please add referencing to your Tabl1,2.

Response: Thank you for reviewing our manuscript! We have added referencing to Table 1 and Table 2.

 

Comments 4: Please improve English .

Response: Thank your for your kind reminding! We have made improvements to the English language of this manuscript on a sentence-by-sentence basis.

Reviewer 2 Report

Comments and Suggestions for Authors

The Dectin-1 signaling pathway has been proposed as a viable treatment option for cancer. The authors discuss both the anti- tumor and pro- tumor role of Dectin-1. They also review attempts to use it as a therapeutic target in cancer treatment.

Minor Comments:

1. The authors did not include any Figures in the article. Figures would have presented complex information (such as the dectin-1 intracellular signalling) more effectively.

2. Lines 82-103: There are no references to related works.

3. Table 1 is understood by itself without the accompanying text. However, why is there no “References” section in Table 1? It would be appropriate to include standard citations in the table.

4. Similarly, Table 2 does not have a 'References' section. Standard citations should be included in the table.

5. All Tables should be cited in the article's main text. The tables should be placed as close as possible to where they first appear in the text. Unfortunately, tables are not listed in the text.

Author Response

Comments 1: The authors did not include any Figures in the article. Figures would have presented complex information (such as the dectin-1 intracellular signalling) more effectively.

Response: Thank you for your constructive advice! We have included a graphic abstract to the manuscript!

 

Comments 2: Lines 82-103: There are no references to related works.

Response: Thank you for your kind reminding! Please check line 107-128 of the revised manuscript. We have added references to the related work.

 

Comments 3 and 4: Table 1 is understood by itself without the accompanying text. However, why is there no “References” section in Table 1? It would be appropriate to include standard citations in the table. Similarly, Table 2 does not have a 'References' section. Standard citations should be included in the table.

Response: Thank you for your kind reminding! We have included citations to Table1, Table2 and added annotations to the tables in the revised manuscript.

 

Comments 5: All Tables should be cited in the article's main text. The tables should be placed as close as possible to where they first appear in the text. Unfortunately, tables are not listed in the text.

Response: Thank you for your kind reminding! We have replaced the tables in the text in the revised manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

1) Prefer to include a more detailed descriptions of immune response of Dectin-1 (i.e., in the paper, it said "enhancing the production of pro-inflammatory cytokines and promoting a more effective immune response against pathogen", it is too vague and I prefer the authors to at least list several pro-inflammatory cytokines(such as IL-1β, IL-6, and TNF-α ) that Dectin-1 stimulates and the immune responses (i.e. macrophage polarization or sth else) it triggers)

2) I hope that the authors could compare/discuss (at least briefly) the Dectin-1 with other antitumor targets. Considering such many different approaches of antitumor research, I don't see the significance of Dectin-1, which is greater than other targets. Authors should mention more about why or why not Dectin-1 is more important than other approaches 

3) Authors only mentioned 1 drugs currently under clinical trial 1 that is associated with Dectin-1. Without any more success stories that even remotely relate to Dectin-1, I don't think that Dectin-1 is an important topic to discuss in the context of cancer research.

Comments on the Quality of English Language

Minor grammar errors detected. Also they need to divide the long paragraphs into subsections for better readability. Difficult to read in large chunk and it shows the writings are not performed in an organized and logical manner.

Author Response

Comments 1:

Prefer to include a more detailed descriptions of immune response of Dectin-1 (i.e., in the paper, it said "enhancing the production of pro-inflammatory cytokines and promoting a more effective immune response against pathogen", it is too vague and I prefer the authors to at least list several pro-inflammatory cytokines(such as IL-1β, IL-6, and TNF-α ) that Dectin-1 stimulates and the immune responses (i.e. macrophage polarization or sth else) it triggers)

 

Response 1:

Thank you for your valuable suggestions. We have made corresponding revisions according to your comments. Please check line 67-81 of the revised manuscript.

 

Comments 2 and 3:

I hope that the authors could compare/discuss (at least briefly) the Dectin-1 with other antitumor targets. Considering such many different approaches of antitumor research, I don't see the significance of Dectin-1, which is greater than other targets. Authors should mention more about why or why not Dectin-1 is more important than other approaches 

Authors only mentioned 1 drugs currently under clinical trial 1 that is associated with Dectin-1. Without any more success stories that even remotely relate to Dectin-1, I don't think that Dectin-1 is an important topic to discuss in the context of cancer research.

 

Response 2 and 3:

Thank you for your valuable suggestions. Our review summarized the dual role of Dectin-1 in tumor biology and its potential implications in tumor therapy, as a receptor previously known for its significant role in antifungal immunity We also explored strategies and possibilities for developing anti-tumor therapies targeting Dectin-1 based on current research evidence, aiming to provide information and insights for oncologists and immunologists interested in this receptor.

Given the genetic and epigenetic diversity of tumors, the heterogeneity of the tumor microenvironment, and the evolving interactions between tumors and the immune system, it is widely accepted that effective tumor treatment should focus on curative surgery, complemented by radiotherapy, chemotherapy, multi-targeted therapies, and immunotherapy to achieve satisfactory control.

As you have noted, research on the role of Dectin-1 in tumor biology is still limited. A search on PubMed for "(Dectin-1) AND (clinical trial)" yields only 13 results. However, in recent years, some high-quality researches published in journals such as Nature Medicine¹, Nature Communication^2-3, and Science Immunology⁴ have provided evidence supporting the important role of Dectin-1 in tumor biology. Furthermore, Dectin-1 is the primary receptor for human recognition of β-glucan, and extensive studies have confirmed the immunomodulatory and anti-tumor effects of β-glucan, suggesting that Dectin-1 may play a significant role in these processes.

In summary, we believe that research on the role of Dectin-1 in tumor biology is still in its early stages. It has the potential to become a novel target for anti-tumor therapy and warrants further investigation by scientists.

As for English language, we have re-polished the manuscript and made the sentences more readable and reasonable. If further improvement is considered needed, we will contact the journal's language polishing service.

Thank you once again for your insightful comments. Best wishes.

 

Reference

1. Daley D, Mani VR, Mohan N, Akkad N, Ochi A, Heindel DW, Lee KB, Zambirinis CP, Pandian GSB, Savadkar S, Torres-Hernandez A, Nayak S, Wang D, Hundeyin M, Diskin B, Aykut B, Werba G, Barilla RM, Rodriguez R, Chang S, Gardner L, Mahal LK, Ueberheide B, Miller G. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat Med. 2017 May;23(5):556-567. doi: 10.1038/nm.4314. Epub 2017 Apr 10. Erratum in: Nat Med. 2021 Dec;27(12):2247-2248. doi: 10.1038/s41591-021-01428-0. PMID: 28394331; PMCID: PMC5419876.
2. Tang C, Sun H, Kadoki M, Han W, Ye X, Makusheva Y, Deng J, Feng B, Qiu D, Tan Y, Wang X, Guo Z, Huang C, Peng S, Chen M, Adachi Y, Ohno N, Trombetta S, Iwakura Y. Blocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression. Nat Commun. 2023 Mar 17;14(1):1493. doi: 10.1038/s41467-023-37229-x. PMID: 36932082; PMCID: PMC10023663.
3. Zhao Y, Chu X, Chen J, Wang Y, Gao S, Jiang Y, Zhu X, Tan G, Zhao W, Yi H, Xu H, Ma X, Lu Y, Yi Q, Wang S. Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. Nat Commun. 2016 Aug 5;7:12368. doi: 10.1038/ncomms12368. PMID: 27492902; PMCID: PMC4980454.
4. Wattenberg MM, Coho H, Herrera VM, Graham K, Stone ML, Xue Y, Chang RB, Cassella C, Liu M, Choi-Bose S, Thomas SK, Choi H, Li Y, Markowitz K, Melendez L, Gianonne M, Bose N, Beatty GL. Cancer immunotherapy via synergistic coactivation of myeloid receptors CD40 and Dectin-1. Sci Immunol. 2023 Nov 17;8(89):eadj5097. doi: 10.1126/sciimmunol.adj5097. Epub 2023 Nov 17. PMID: 37976347; PMCID: PMC11034815.

Reviewer 2 Report

Comments and Suggestions for Authors

Most of my comments were considered. I have no further suggestions.

Author Response

Thank you for reviewing our manuscript and your constructive suggestions. 

Best Wishes.

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

ok accept, no further comments