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Immune Biomarkers in Solid Tumors: From Peripheral Blood Parameters to Tissue-Based Indicators for Prognosis and Therapy Response

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: 31 December 2026 | Viewed by 7492

Special Issue Editors

Dr. Ioannis P. Trontzas

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Guest Editor
3rd Department of Internal Medicine, Sotiria General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
Interests: cancer; lung cancer; immunotherapy; cancer biomarkers
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Konstantinos Syrigos

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Guest Editor
Third Department of Internal Medicine, Sotiria Hospital, National and Kapodistrian University of Athens, School of Medicine, 11527 Athens, Greece
Interests: cancer; lung cancer; immunotherapy; immune-related adverse events
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The tumor microenvironment and systemic immune responses play critical roles in the progression, prognosis, and therapeutic response of solid malignancies. In recent years, the evaluation of peripheral blood immune parameters—such as immune cell subsets, cytokines, and soluble markers—has gained prominence as a minimally invasive approach to guide clinical decision-making. Concurrently, tissue-based immune biomarkers, including immune checkpoint molecules like PD-L1, have become integral components of predictive and prognostic models across a range of solid tumors.

This Special Issue aims to highlight advances in the identification, validation, and clinical implementation of both circulating and histological immune biomarkers. We welcome original research, reviews, and perspectives focusing on the prognostic value, predictive utility, and mechanistic insights of immune biomarkers, with particular interest in studies that bridge systemic and tumor-localized immune profiling to optimize therapeutic strategies in solid tumors.

Dr. Ioannis P. Trontzas
Prof. Dr. Konstantinos Syrigos
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immune biomarkers
  • solid tumors
  • peripheral blood immune parameters
  • circulating immune cells
  • cytokines
  • tissue-based biomarkers
  • immune checkpoint molecules
  • prognostic biomarkers
  • predictive biomarkers
  • tumor microenvironment
  • immunotherapy response
  • translational oncology

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Published Papers (4 papers)

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Research

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20 pages, 2032 KB  
Article
Immunohistochemical Expression of IDO and PD-L1 in Distinct Compartments of Breast Cancer Tissue: Correlation with Clinicopathological Features and Outcomes
by Nikolaos Syrigos, Alexandros Mougiakos, Anastasia Konstantinidou, Emmanouil Panagiotou, Anastasia Karachaliou, Eleni Fyta, Ioannis Vamvakaris, Evangelia Karagianni, Elias Kotteas, Sophocles Lanitis, Christos Markopoulos, Theodoros Troupis and Dimitra Grapsa
Cancers 2026, 18(7), 1180; https://doi.org/10.3390/cancers18071180 - 7 Apr 2026
Viewed by 628
Abstract
Background: Indoleamine 2,3-dioxygenase (IDO) is an immune checkpoint that has been shown to play a key immunomodulatory role in various solid tumors, including breast cancer (BC). Although increased IDO expression has been previously observed in some BC subtypes, mainly triple-negative BC (TNBC), [...] Read more.
Background: Indoleamine 2,3-dioxygenase (IDO) is an immune checkpoint that has been shown to play a key immunomodulatory role in various solid tumors, including breast cancer (BC). Although increased IDO expression has been previously observed in some BC subtypes, mainly triple-negative BC (TNBC), the clinical relevance of this protein across the entire range of BC and its exact correlations with other immune checkpoints remain to be elucidated. We herein aimed to further investigate the differential expression patterns of IDO and programmed death-ligand 1 (PD-L1) in variable BC subtypes and in distinct compartments of breast cancer tissue, and to explore their potential associations with standard patient- and tumor-related clinicopathological parameters as well as prognosis. Methods: This was a retrospective multi-center cohort study of 150 female patients with BC. The clinicopathological parameters analyzed were retrieved from the medical records of patients while sections from archival formalin-fixed, paraffin-embedded (FFPE) tissue blocks were also obtained for the performance of immunohistochemistry. The expression of IDO and PD-L1 was evaluated separately on tumor cells (IDO/CA, PD-L1/CA), lymphocytes (IDO/L, PD-L1/L) and stromal cells (IDO/S, PD-L1/S) and the results were correlated with the remaining clinical and pathological features of patients, as well as with local recurrence, metastasis and survival. Results: The mean age of patients was 59.5 years (SD = 13.4 years). Positive expression of IDO/CA, IDO/L and IDO/S was found in 6%, 93.3% and 90.7% of tissue samples, respectively, while 4%, 11.2% and 6.7% of tumors were positive for PD-L1/CA, PD-L1/L and PD-L1/S, respectively. A significantly higher rate of positive IDO/CA expression was observed in triple-negative BC (TNBC) patients (p = 0.037). Positive expression of IDO-CA was also significantly associated with positivity for PD-L1/L and PD-L1/S (p = 0.001 and p = 0.015, respectively). Multivariable logistic regression analysis showed independent correlations between IDO/CA and IDO/L and the presence of invasive ductal carcinoma (IDC) (OR = 1.10; p = 0.026) and N1 status (OR = 10.93; p = 0.039), respectively, IDO/S and both N1 (OR = 14.64; p = 0.018) and positive HER2 status (OR = 6.11; p = 0.019), PD-L1/L and high Ki67 (OR = 7.96; p = 0.001) as well as negative ER (OR = 0.08; 0.003) and PR status (OR = 0.09; p = 0.002), PD-L1/S and both NST (no special type) histology (OR = 4.68; p = 0.032) and negative ER status (OR = 0.21; p = 0.044). No statistically significant associations were observed between the expression patterns of the examined biomarkers and recurrence, metastasis or survival. Conclusions: In our study, IDO expression on tumor cells was predominantly observed in TNBC and was found to correlate with PD-L1 expression in the lymphocytic and stromal compartments. Furthermore, expression of PD-L1 among lymphocytes was found to independently correlate with unfavorable clinicopathological parameters, including high proliferation rate and negative hormone receptor status. Full article
(This article belongs to the Special Issue Immune Biomarkers in Solid Tumors: From Peripheral Blood Parameters to Tissue-Based Indicators for Prognosis and Therapy Response)
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13 pages, 1957 KB  
Article
Combinatorial Analysis of CD4+Tregs, CD8+Teffs, and Inflammatory Indices Predict Response to ICI in ES-SCLC Patients
by Anastasia Xagara, Konstantinos Tsapakidis, Vassileios Papadopoulos, Alexandros Kokkalis, Evangelia Chantzara, Chryssovalantis Aidarinis, Alexandros Lazarou, George Christodoulopoulos, Matina Perifanou-Sotiri, Dimitris Verveniotis, Vasiliki Rammou, Maria Smaragdi Vlachou, Galatea Kallergi, Alexandra Markou, Ioannis Samaras, Filippos Koinis, Emmanouil Saloustros and Athanasios Kotsakis
Cancers 2026, 18(2), 192; https://doi.org/10.3390/cancers18020192 - 7 Jan 2026
Viewed by 668
Abstract
Background: Small-cell lung cancer (SCLC) is an aggressive type of lung cancer, and several factors are currently used to predict poor outcomes, including performance status (PS), extensive-stage disease, male sex, advanced age, and elevated lactate dehydrogenase (LDH) levels. In this study, we [...] Read more.
Background: Small-cell lung cancer (SCLC) is an aggressive type of lung cancer, and several factors are currently used to predict poor outcomes, including performance status (PS), extensive-stage disease, male sex, advanced age, and elevated lactate dehydrogenase (LDH) levels. In this study, we aimed to explore the role of Tegs and inflammatory indices, such as CRP and NLR, in predicting response to immunotherapy. Methods: Fifty-one therapy-naïve ES-SCLC patients and ten healthy donors were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and stained with fluorochrome-conjugated monoclonal antibodies. Multicolor flow cytometry was performed to determine the levels of CD8+ T cells and CD4+ Tregs, as well as their correlation with inflammatory indices and clinical outcomes. Results: ES-SCLC patients harbored higher percentages of CD8+ Teffs (p = 0.005) and FOXP3+ Tregs (p < 0.0001) in circulation before therapy compared with healthy donors. In addition, high levels of CD3+CD8+ T effectors were associated with longer PFS (p = 0.018) and longer OS (p = 0.012) compared with patients bearing low levels, while Tregs were not found to be predictive. More importantly, a survival benefit was observed in ES-SCLC patients with a low Treg/Teff ratio, as longer OS was observed in those with high percentages of CD8+ Teffs and low FOXP3+CTLA-4+ Tregs (p = 0.014) compared with those bearing low CD8+ Teffs and high FOXP3+CTLA-4+ Tregs. A low Treg/Teff ratio was further associated with low eosinophil levels and a low NLR before treatment initiation. Conclusions: These findings suggest a novel, easily obtainable blood-based signature that may help predict response to ICIs in ES-SCLC patients. Full article
(This article belongs to the Special Issue Immune Biomarkers in Solid Tumors: From Peripheral Blood Parameters to Tissue-Based Indicators for Prognosis and Therapy Response)
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15 pages, 1297 KB  
Article
Pancreatic Cancer and Benign Pancreatic Cystic Lesions: Differences in Cytokines, Growth Factors, and Immunological Markers Concentrations in Serum and Cystic Fluid
by Ewa Grudzińska, Paweł Szmigiel, Karolina Majewska, Sławomir Mrowiec and Zenon P. Czuba
Cancers 2025, 17(17), 2783; https://doi.org/10.3390/cancers17172783 - 26 Aug 2025
Cited by 1 | Viewed by 1547
Abstract
Background: Pancreatic cystic lesions may be benign and require observation or cancerous, with high mortality, requiring risky surgery. Diagnosis is often difficult, and the search for biomarkers to differentiate pancreatic cancer from other lesions is ongoing. Methods: 60 consecutive patients, operated on due [...] Read more.
Background: Pancreatic cystic lesions may be benign and require observation or cancerous, with high mortality, requiring risky surgery. Diagnosis is often difficult, and the search for biomarkers to differentiate pancreatic cancer from other lesions is ongoing. Methods: 60 consecutive patients, operated on due to histopathologically confirmed pancreatic cancer or due to pancreatic cystic lesions, were analyzed. The concentrations of 16 immunological factors (sHER-2neu, sEGFR, sIL-6Ra, follistatin, FGF-basic, sVEGFR-2, PECAM-1, PDGF-AB BB, prolactin, G-CSF, HGF, sTIE-2, SCF, sVEGFR-1, osteopontin, and leptin) were assessed in both serum and cystic fluid and compared between the groups. Results: Lower PDGF-AB/BB and leptin concentrations in serum, as well as lower sTIE-2, osteopontin, and leptin levels, were associated with cancer. In cystic tumors, for some factors, significant differences between cancerous and benign lesions were found when the differences in cystic fluid and serum concentrations were compared. Conclusions: PDGF-AB/BB, leptin, sTIE-2, and osteopontin, as well as the comparison of serum/cystic fluid concentrations of immunological factors, might be useful for pancreatic cystic tumor diagnosis. However, this requires confirmation in a larger study. Full article
(This article belongs to the Special Issue Immune Biomarkers in Solid Tumors: From Peripheral Blood Parameters to Tissue-Based Indicators for Prognosis and Therapy Response)
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Review

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19 pages, 965 KB  
Review
Immune Biomarkers for Checkpoint Blockade in Solid Tumors: Transitioning from Tissue to Peripheral Blood Monitoring and Future Integrated Strategies
by Ioannis P. Trontzas and Konstantinos N. Syrigos
Cancers 2025, 17(16), 2639; https://doi.org/10.3390/cancers17162639 - 13 Aug 2025
Cited by 8 | Viewed by 3919
Abstract
Immunotherapy with immune checkpoint inhibitors has changed the treatment landscape in many solid tumors. Despite the unprecedent success, many patients will develop primary or secondary resistance to treatment or will hold up therapy due to the emerging immune-related toxicity. Traditionally, tissue-based immune biomarkers, [...] Read more.
Immunotherapy with immune checkpoint inhibitors has changed the treatment landscape in many solid tumors. Despite the unprecedent success, many patients will develop primary or secondary resistance to treatment or will hold up therapy due to the emerging immune-related toxicity. Traditionally, tissue-based immune biomarkers, such as PD-L1 expression, have been used to select patients who will benefit most from immunotherapy. However, these markers demonstrate major limitations, such as tumor heterogeneity and sample constraints. In addition, they do not reflect the dynamic interplay of tumor and hosts immune response during treatment. Peripheral blood immunomarkers offer a minimally invasive, real-time assessment of the immune system and its interaction with the tumor. Integration of traditional tissue-based and peripheral blood markers coupled with the recent developments in computational platforms, artificial intelligence, and machine learning models may provide more successful biomarkers for prognosis, prediction of immunotherapy-related outcomes, the early evaluation of forthcoming disease progression, and the prediction of the emerging immune-related adverse events. Despite the promising developments in the field of immune biomarkers, several issues including assay standardization, clinical validation, and biological variability should be addressed to improve personalized immunotherapy approaches. In this comprehensive review we provide an update on immune biomarker evolution, and we discuss the current limitations and future directions. Full article
(This article belongs to the Special Issue Immune Biomarkers in Solid Tumors: From Peripheral Blood Parameters to Tissue-Based Indicators for Prognosis and Therapy Response)
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