Local and systemic immune profiles in tumors

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Contacts: Svetlana Aleksandrovna Kulyova Kulevadoc@yandex.ru

The immune system is able to destroy tumors, but the progression of the malignant process indicates a violation of this mechanism. Analysis of literature data on the prognostic effect of different microenvironment T subpopulations shows that cytotoxic CD8+-T cells and memory T cells associated with Th1-type immune response correlate with good clinical course in most cancer types studied. On the other hand, the prognostic value of Th2, Th17 or Treg cell populations is inconsistent and varies depending on the type and stage of malignancy. Overall, these results strongly suggest that tumor behavior should now be viewed as the result of a balance between an invasive tumor process and a coordinated macroorganism immune response. In children, the microenvironment of solid tumors is heterogeneous, dynamic, and distinct from the microenvironment of neoplasias found in adults. Due to the low mutation burden, tumors in children have a limited set of neoantigens that could be recognized, and a small number of infiltrating T cells are represented in their tumor environment. Traditional biopsy does not always reflect tumor heterogeneity, so the focus shifts to peripheral blood testing. Biomarkers in the blood allow reassessment at different time points, they are readily available and their sampling is less invasive for patients. In addition, they can provide more information on immune status and assist in assessing a patient’s potential to develop effective immunity against a tumor. The article presents a modern view of immunological landscape of malignant tumors with a complex network of various cell populations and interactions between them.

About the authors

Svetlana A. Kulyova

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia; Saint Petersburg State Pediatric Medical University, Ministry of Health Russia

Author for correspondence.
Email: Kulevadoc@yandex.ru
ORCID iD: 0000-0003-0390-8498
Russian Federation, 68 Leningradskaya St., Pesochny Settlement, Saint Petersburg 197758; 2 Litovskaya St., Saint Petersburg 194100

Olga E. Savelieva

Saint Petersburg State Pediatric Medical University, Ministry of Health Russia

Email: olga_chechina@mail.ru
ORCID iD: 0000-0002-0301-8455
Russian Federation, 2 Litovskaya St., Saint Petersburg 194100

Irina A. Baldueva

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

Email: biahome@mail.ru
ORCID iD: 0000-0002-7472-4613
Russian Federation, 68 Leningradskaya St., Pesochny Settlement, Saint Petersburg 197758

Ksenia M. Borokshinova

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

Email: bk0807@bk.ru
ORCID iD: 0000-0002-5004-1543
Russian Federation, 68 Leningradskaya St., Pesochny Settlement, Saint Petersburg 197758

Elena A. Mikhaylova

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

Email: helen_mikhaylova@mail.ru
ORCID iD: 0000-0003-1081-5118
Russian Federation, 68 Leningradskaya St., Pesochny Settlement, Saint Petersburg 197758

Tatyana L. Nekhaeva

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

Email: nehaeva151274@mail.ru
ORCID iD: 0000-0002-7826-4861
Russian Federation, 68 Leningradskaya St., Pesochny Settlement, Saint Petersburg 197758

Alika A. Kulyova

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

Email: kuleva.alika@mail.ru
ORCID iD: 0000-0001-9886-1420
Russian Federation, 68 Leningradskaya St., Pesochny Settlement, Saint Petersburg 197758

Evgeny M. Senchurov

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia; Saint Petersburg State Pediatric Medical University, Ministry of Health Russia

Email: senchurov85@mail.ru
ORCID iD: 0000-0002-6742-5754
Russian Federation, 68 Leningradskaya St., Pesochny Settlement, Saint Petersburg 197758; 2 Litovskaya St., Saint Petersburg 194100

References

  1. Vogelstein B., Fearon E.R., Hamilton S.R. et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319(9):525–32. doi: 10.1056/NEJM198809013190901
  2. Folkman J., Hahnfeldt P., Hlatky L. Cancer: looking outside the genome. Nat Rev Mol Cell Biol 2000;1(1):76–9. doi: 10.1038/35036100
  3. Vogelstein B., Papadopoulos N., Velculescu V.E. et al. Cancer genome landscapes. Science 2013;339(6127):1546–58. doi: 10.1126/science.1235122
  4. Hanahan D., Weinberg R.A. The hallmarks of cancer. Cell 2000;100(1):57–70. doi: 10.1016/s0092-8674(00)81683-9
  5. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. doi: 10.1016/j.cell.2011.02.013
  6. Sonnenschein C., Soto A.M. The death of the cancer cell. Cancer Res 2011;71(13):4334–7. doi: 10.1158/0008-5472.CAN-11-0639
  7. Ehrlich P. Über den jetzigen Stand der Karzinomforschung. Ned Tijdschr Geneeskd 1909;5:273.
  8. Burnet F.M. The concept of immunological surveillance. Prog Exp Tumor Res 1970;13:1. doi: 10.1159/000386035
  9. Dunn G.P., Old L.J., Schreiber R.D. The three Es of cancer immunoediting. Annu Rev Immunol 2004;22:329–60. doi: 10.1146/annurev.immunol.22.012703.104803
  10. Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011;331(6014):1565–70. doi: 10.1126/science.1203486
  11. Gubin M.M., Vesely M.D. Cancer immunoediting in the era of immuno-oncology. Clin Cancer Res 2022;28(18):3917–28. doi: 10.1158/1078-0432.CCR-21-1804
  12. Xiao Y., Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol Ther 2021;221:107753. doi: 10.1016/j.pharmthera.2020.107753
  13. Toledo B., Zhu Chen L., Paniagua-Sancho M. et al. Deciphering the performance of macrophages in tumour microenvironment: a call for precision immunotherapy. J Hematol Oncol 2024;17(1):44. doi: 10.1186/s13045-024-01559-0
  14. Arneth B. Tumor microenvironment. Medicina 2020;56:15. doi: 10.3390/medicina56010015
  15. Kulyova S.A., Druy A.E. Immunology and prospects for immunotherapy of primary CNS malignancies: adoptive cell therapy and virotherapy. Voprosy onkologii = Oncology Issues 2020;3(66):218–22. (In Russ.). doi: 10.37469/0507-3758-2020-66-3-218-222
  16. Rőszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm 2015;2015:816460. doi: 10.1155/2015/816460
  17. Lo Sicco C., Reverberi D., Balbi C. et al. Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med 2017;6(3):1018–28. doi: 10.1002/sctm.16-0363
  18. Atri C., Guerfali F.Z., Laouini D. Role of human macrophage polarization in inflammation during infectious diseases. Int J Mol Sci 2018;19(6):1801. doi: 10.3390/ijms19061801
  19. Caronni N., La Terza F., Vittoria F.M. et al. IL-1beta(+) macrophages fuel pathogenic inflammation in pancreatic cancer. Nature 2023;623(7986):415–22. doi: 10.1038/s41586-023-06685-2
  20. Ruffell B., Affara N.I., Coussens L.M. Differential macrophage programming in the tumor microenvironment. Trends Immunol 2012;33(3):119–26. doi: 10.1016/j.it.2011.12.001
  21. Biswas S.K., Allavena P., Mantovani A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol 2013;35(5):585–600. doi: 10.1007/s00281-013-0367-7
  22. Kerneur C., Cano C.E., Olive D. Major pathways involved in macrophage polarization in cancer. Front Immunol 2022;13:1026954. doi: 10.3389/fimmu.2022.1026954
  23. Fridman W.H., Pagès F., Sautès-Fridman C., Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012;12:298–306. doi: 10.1038/nrc3245
  24. Meireson A., Tavernier S.J., Van Gassen S. et al. Immune monitoring in melanoma and urothelial cancer patients treated with anti-PD-1 immunotherapy and SBRT discloses tumor specific immune signatures. Cancers (Basel) 2021;13(11):2630. doi: 10.3390/cancers13112630
  25. Baessler A., Vignali D.A.A. T cell exhaustion. Annu Rev Immunol 2024;42(1):179–206. doi: 10.1146/annurev-immunol-090222-110914
  26. Postow M.A., Callahan M.K., Wolchok J.D. Immune checkpoint blockade in cancer therapy. J Clin Oncol 2015;33(17):1974–82. doi: 10.1200/JCO.2014.59.4358
  27. Pauken K.E., Wherry E.J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol 2015;36(4):265–76. doi: 10.1016/j.it.2015.02.008
  28. MacCarty W.C. Principles of prognosis in cancer. JAMA 1931;96:30.
  29. Bai Z., Zhou Y., Ye Z. et al. Tumor-infiltrating lymphocytes in colorectal cancer: the fundamental indication and application on immunotherapy. Front Immunol 2022;14;12:808964. doi: 10.3389/fimmu.2021.808964
  30. Zhang Y., Wu D., Zhang Z. et al. Impact of lymph node metastasis on immune microenvironment and prognosis in colorectal cancer liver metastasis: insights from multiomics profiling. Br J Cancer 2025;132(6):513–24. doi: 10.1038/s41416-024-02921-2
  31. Maibach F., Sadozai H., Seyed Jafari S.M. et al. Tumor-infiltrating lymphocytes and their prognostic value in cutaneous melanoma. Front Immunol 2020;11:2105. doi: 10.3389/fimmu.2020.02105
  32. Zhao H., Zhao Y., Zhang S. et al. Effects of immunogenic cell death-inducing chemotherapeutics on the immune cell activation and tertiary lymphoid structure formation in melanoma. Front Immunol 2024;15:1302751. doi: 10.3389/fimmu.2024.1302751
  33. Dieci M.V., Miglietta F., Guarneri V. Immune infiltrates in breast cancer: recent updates and clinical implications. Cells 2021;10(2):223. doi: 10.3390/cells10020223
  34. Jass J.R. Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 1986;39(6):585–9. doi: 10.1136/jcp.39.6.585
  35. Sarivalasis A., Morotti M., Mulvey A. et al. Cell therapies in ovarian cancer. Ther Adv Med Oncol 2021;13:17588359211008399. doi: 10.1177/17588359211008399
  36. Jiang A.M., Ren M.D., Liu N. et al. Tumor mutation burden, immune cell infiltration, and construction of immune-related genes prognostic model in head and neck cancer. Int J Med Sci 2021;18(1): 226–38. doi: 10.7150/ijms.51064
  37. Tian Y., Liu C., Yang W. et al. Highlighting immune features of the tumor ecosystem and prognostic value of Tfh and Th17 cell infiltration in head and neck squamous cell carcinoma by single-cell RNA-seq. Cancer Immunol Immunother 2024;73(10):187. doi: 10.1007/s00262-024-03767-6
  38. Cheng Z., Yang C., Zhao Q. et al. Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer. Cancer Sci 2024;115(6):1979–88. doi: 10.1111/cas.16142
  39. Jin Y.W., Hu P. Tumor-infiltrating CD8 T cells predict clinical breast cancer outcomes in young women. Cancers (Basel) 2020;12(5):1076. doi: 10.3390/cancers12051076
  40. Xu X., Tan Y., Qian Y. et al. Clinicopathologic and prognostic significance of tumor-infiltrating CD8+ T cells in patients with hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore) 2019;98(2):e13923. doi: 10.1097/MD.0000000000013923
  41. Zhang J., Wang Y.F., Wu B. et al. Intraepithelial attack rather than intratumorally infiltration of CD8+T lymphocytes is a favorable prognostic indicator in pancreatic ductal adenocarcinoma. Curr Mol Med 2017;17(10):689–98. doi: 10.2174/1566524018666180308115705
  42. Kärjä V., Aaltomaa S., Lipponen P. et al. Tumour-infiltrating lymphocytes: a prognostic factor of PSA-free survival in patients with local prostate carcinoma treated by radical prostatectomy. Anticancer Res 2005;25(6С):4435–8.
  43. Toki M.I., Merritt C.R., Wong P.F. et al. High-plex predictive marker discovery for melanoma immunotherapy-treated patients using digital spatial profiling. Clin Cancer Res 2019;25(18):5503–12. doi: 10.1158/1078-0432.CCR-19-0104
  44. Giatromanolaki A., Anestopoulos I., Panayiotidis M.I. et al. Prognostic relevance of the relative presence of CD4, CD8 and CD20 expressing tumor infiltrating lymphocytes in operable non-small cell lung cancer patients. Anticancer Res 2021;41(8):3989–95. doi: 10.21873/anticanres.15196
  45. He M., He Q., Cai X. et al. Intratumoral tertiary lymphoid structure (TLS) maturation is influenced by draining lymph nodes of lung cancer. J Immunother Cancer 2023;11(4):e005539. doi: 10.1136/jitc-2022-005539
  46. Shigehara K., Kawai N., Shirosaki T. et al. The size of CD8+ infiltrating T cells is a prognostic marker for esophageal squamous cell carcinoma. Sci Rep 2025;15(1):26638. doi: 10.1038/s41598-025-10885-3
  47. Bell P.D., Pai R.K. Immune response in colorectal carcinoma: a review of its significance as a predictive and prognostic biomarker. Histopathology 2022;81(6):696–714. doi: 10.1111/his.14713
  48. Liu J., Li J., Luo F. et al. The Predictive Value of CD3+/CD8+ lymphocyte infiltration and PD-L1 expression in colorectal cancer. Curr Oncol 2023;30(11):9647–59. doi: 10.3390/curroncol30110699
  49. Schmitt M., Greten F.R. The inflammatory pathogenesis of colorectal cancer. Nat Rev Immunol 2021;21(10):653–67. doi: 10.1038/s41577-021-00534-x
  50. Dai S., Zeng H., Liu Z. et al. Intratumoral CXCL13+CD8+T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma. J Immunother Cancer 2021;9(2):e001823. doi: 10.1136/jitc-2020-001823
  51. Monjaras-Avila C.U., Lorenzo-Leal A.C., Luque-Badillo A.C. et al. The tumor immune microenvironment in clear cell renal cell carcinoma. Int J Mol Sci 2023;24(9):7946. doi: 10.3390/ijms24097946
  52. Becht E., Giraldo N.A., Dieu-Nosjean M.C. et al. Cancer immune contexture and immunotherapy. Curr Opin Immunol 2016;39:7–13. doi: 10.1016/j.coi.2015.11.009
  53. Jacqueline C., Bourfia Y., Hbid H. et al. Interactions between immune challenges and cancer cells proliferation: timing does matter! Evol Med Public Health 2016;2016(1):299–311. doi: 10.1093/emph/eow025
  54. Santavanond J.P., Rutter S.F., Atkin-Smith G.K., Poon I.K.H. Apoptotic bodies: mechanism of formation, isolation and functional Relevance. Subcell Biochem 2021;97:61–88. doi: 10.1007/978-3-030-67171-6_4
  55. Mylvaganam G., Yanez A.G., Maus M., Walker B.D. Toward T Cell-mediated control or elimination of HIV reservoirs: lessons from cancer immunology. Front Immunol 2019;10:2109. doi: 10.3389/fimmu.2019.02109
  56. Waldman A.D., Fritz J.M., Lenardo M.J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 2020;20(11):651–68. doi: 10.1038/s41577-020-0306-5
  57. Du X., Wang X., Cui K. et al. Tanshinone IIA and astragaloside IV inhibit miR-223/JAK2/STAT1 signalling pathway to alleviate lipopolysaccharide-induced damage in nucleus pulposus cells. Dis Markers 2021;12:6554480. doi: 10.1155/2021/6554480
  58. Alhouayek M., Rankin L., Gouveia-Figueira S., Fowler C.J. Interferon γ treatment increases endocannabinoid and related N-acylethanolamine levels in T84 human colon carcinoma cells. Br J Pharmacol 2019;176(10):1470–80. doi: 10.1111/bph.14135
  59. Sharapova T.N., Romanova E.A., Ivanova O.K. et al. Cytokines TNFα, IFNγ and IL-2 are responsible for signal transmission from the innate immunity protein Tag7 (PGLYRP1) to cytotoxic effector lymphocytes. Cells 2020;9(12):2602. doi: 10.3390/cells9122602
  60. Nathan C., Cunningham-Bussel A. Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat Rev Immunol 2013;13(5):349–61. doi: 10.1038/nri3423
  61. Li M., Zhu W., Lu Y. et al. Identification and validation of a CD4+ T cell-related prognostic model to predict immune responses in stage III-IV colorectal cancer. BMC Gastroenterol 2025;25(1):153. doi: 10.1186/s12876-025-03716-2
  62. Mai Z., Lin Y., Lin P. et al. Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy. Cell Death Dis 2024;15(5):307. doi: 10.1038/s41419-024-06697-4
  63. Zhang L., Chen X., Zu S., Lu Y. Characteristics of circulating adaptive immune cells in patients with colorectal cancer. Sci Rep 2022;12(1):18166. doi: 10.1038/s41598-022-23190-0
  64. Sanz-Pamplona R., Melas M., Maoz A. et al. Lymphocytic infiltration in stage II microsatellite stable colorectal tumors: a retrospective prognosis biomarker analysis. PLoS Med 2020;17(9):e1003292. doi: 10.1371/journal.pmed.1003292
  65. Picard E., Verschoor C.P., Ma G.W., Pawelec G. Relationships between immune landscapes, genetic subtypes and responses to immunotherapy in colorectal cancer. Front Immunol 2020;11:369. doi: 10.3389/fimmu.2020.00369
  66. Nagtegaal I.D., Marijnen C.A., Kranenbarg E.K. et al. Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect – a histopathological and immunohistochemical study. BMC Cancer 2001;1:7. doi: 10.1186/1471-2407-1-7
  67. Seebauer C.T., Brunner S., Glockzin G. et al. Peritoneal carcinomatosis of colorectal cancer is characterized by structural and functional reorganization of the tumor microenvironment inducing senescence and proliferation arrest in cancer cells. Oncoimmunology 2016;5(12):e1242543. doi: 10.1080/2162402X.2016.1242543
  68. Huang J., Zhang J.L., Ang L. et al. Proposing a novel molecular subtyping scheme for predicting distant recurrence-free survival in breast cancer post-neoadjuvant chemotherapy with close correlation to metabolism and senescence. Front Endocrinol (Lausanne) 2023;14:1265520. doi: 10.3389/fendo.2023.1265520
  69. Shahrouzi P., Forouz F., Mathelier A. et al. Copy number alterations: a catastrophic orchestration of the breast cancer genome. Trends Mol Med 2024;30(8):750–64. doi: 10.1016/j.molmed.2024.04.017
  70. Wang Y.A., Neff R., Song W.M. et al. Multi-omics-based analysis of high grade serous ovarian cancer subtypes reveals distinct molecular processes linked to patient prognosis. FEBS Open Bio 2023;13(4):617–37. doi: 10.1002/2211-5463.13553
  71. Zob D.L., Augustin I., Caba L. et al. Genomics and epigenomics in the molecular biology of melanoma – a prerequisite for biomarkers studies. Int J Mol Sci 2022;24(1):716. doi: 10.3390/ijms24010716
  72. Horti-Oravecz K., Kelemen I., Grolmusz K.V. The role of immunosurveillance and immunoediting in hereditary cancer predisposition syndromes. Magy Onkol 2025;69(1):25–33. (In Hungarian).
  73. Vroman H., van Uden D., Bergen I.M. et al. Tnfaip3 expression in pulmonary conventional type 1 Langerin-expressing dendritic cells regulates T helper 2-mediated airway inflammation in mice. Allergy 2020;75(10):2587–98. doi: 10.1111/all.14334
  74. Miska J., Lui J.B., Toomer K.H. et al. Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines. J Exp Med 2018;215(3):841–58. doi: 10.1084/jem.20171971
  75. Germain C., Gnjatic S., Dieu-Nosjean M.C. Tertiary lymphoid structure-associated B cells are key players in anti-tumor immunity. Front Immunol 2015;6:67. doi: 10.3389/fimmu.2015.00067
  76. De Lima P.O., Dos Santos F.V., Oliveira D.T. et al. Effect of eosinophil cationic protein on human oral squamous carcinoma cell viability. Mol Clin Oncol 2015;3(2):353–6. doi: 10.3892/mco.2014.477
  77. Fu Y., Lin Q., Zhang Z., Zhang L. Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity. Acta Pharm Sin B 2020;10(3):414–33. doi: 10.1016/j.apsb.2019.08.010
  78. Feng B., Bai Z., Zhou X. et al. The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer. Nature 2024;634(8034):712–20. doi: 10.1038/s41586-024-07962-4
  79. Hammoud M.K., Dietze R., Pesek J. et al. Arachidonic acid, a clinically adverse mediator in the ovarian cancer microenvironment, impairs JAK-STAT signaling in macrophages by perturbing lipid raft structures. Mol Oncol 2022;16(17):3146–66. doi: 10.1002/1878-0261.13221
  80. Brunetto E., De Monte L., Balzano G. et al. The IL-1/IL-1 receptor axis and tumor cell released inflammasome adaptor ASC are key regulators of TSLP secretion by cancer associated fibroblasts in pancreatic cancer. J Immunother Cancer 2019;7(1):45. doi: 10.1186/s40425-019-0521-4
  81. Murakami Y., Saito H., Shimizu S. et al. Neutrophil-to-lymphocyte ratio as a prognostic indicator in patients with unresectable gastric cancer. Anticancer Res 2019;39(5):2583–9. doi: 10.21873/anticanres.13381
  82. Sæle A.K., Svanøe A.A., Askeland C. et al. Reduced GATA3 expression associates with immuno-metabolic alterations and aggressive features in breast cancer. J Pathol Clin Res 2025;11(6):e70050. doi: 10.1002/2056-4538.70050
  83. Adam M., Bekuretsion Y., Gebremedhin A. et al. Evidence for distinct mechanisms of immune suppression in EBV-positive and EBV-negative Hodgkin lymphoma. J Clin Exp Hematop 2023;63(4):230–9. doi: 10.3960/jslrt.23037
  84. Overacre-Delgoffe A.E., Bumgarner H.J., Cillo A.R. et al. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. Immunity 2021;54(12):2812–24.e4. doi: 10.1016/j.immuni.2021.11.003
  85. Butcher M.J., Zhu J. Recent advances in understanding the Th1/Th2 effector choice. Fac Rev 2021;10:30. doi: 10.12703/r/10-30
  86. Capone A., Naro C., Bianco M. et al. Systems analysis of human T helper17 cell differentiation uncovers distinct time-regulated transcriptional modules. iScience 2021;24(5):102492. doi: 10.1016/j.isci.2021.102492
  87. Murcia R.Y., Vargas A., Lavoie J.P. The interleukin-17 induced activation and increased survival of equine neutrophils is insensitive to glucocorticoids. PLoS One 2016;11(5):e0154755. doi: 10.1371/journal.pone.0154755
  88. Cremonesi E., Governa V., Garzon J.F.G. et al. Gut microbiota modulate T cell trafficking into human colorectal cancer. Gut 2018;67(11):1984–94. doi: 10.1136/gutjnl-2016-313498
  89. Liao H., Chang X., Gao L. et al. IL-17A promotes tumorigenesis and upregulates PD-L1 expression in non-small cell lung cancer. J Transl Med 2023;21(1):828. doi: 10.1186/s12967-023-04365-3
  90. Gheshlaghi A., Haghshenas M.R., Safarpour A.R. et al. IL-17 genetic variations increase the risk of cirrhotic/hepatocellular carcinoma in patients with hepatitis B virus infection. Iran J Immunol 2021;18(2):130–40. doi: 10.22034/iji.2021.88020.1852
  91. Kiraz Y., Baran Y., Nalbant A. T cells in tumor microenvironment. Tumour Biol 2016;37(1):39–45. doi: 10.1007/s13277-015-4241-1
  92. Hu J., Toyozumi T., Murakami K. et al. Prognostic value of tumor-infiltrating lymphocytes and PD-L1 expression in esophageal squamous cell carcinoma. Cancer Med 2024;13(17):e70179. doi: 10.1002/cam4.70179
  93. Nelson W.G., Brawley O.W., Isaacs W.B. et al. Health inequity drives disease biology to create disparities in prostate cancer outcomes. J Clin Invest 2022;132(3):e155031. doi: 10.1172/JCI155031
  94. Novysedlak R., Guney M., Al Khouri M. et al. The immune microenvironment in prostate cancer: a comprehensive review. Oncology 2025;103(6):521–45. doi: 10.1159/000541881
  95. Nagy N.A., Hafkamp F.M.J., Sparrius R. et al. Retinoic acid-loaded liposomes induce human mucosal CD103+ dendritic cells that inhibit Th17 cells and drive regulatory T-cell development in vitro. Eur J Immunol 2024;54(5):e2350839. doi: 10.1002/eji.202350839
  96. Mills K.H.G. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol 2023;23(1):38–54. doi: 10.1038/s41577-022-00746-9
  97. Caramalho Í., Nunes-Cabaço H., Foxall R.B., Sousa A.E. Regulatory T-cell development in the human thymus. Front Immunol 2015;6:395. doi: 10.3389/fimmu.2015.00395
  98. Gootjes C., Zwaginga J.J., Roep B.O., Nikolic T. Defining human regulatory T cells beyond FOXP3: the need to combine phenotype with function. Cells 2024;13(11):941. doi: 10.3390/cells13110941
  99. Curiel T.J., Coukos G., Zou L. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10(9):942–9. doi: 10.1038/nm1093
  100. Wang Z., Xie Z., Mou Y. et al. TIM-4 increases the proportion of CD4+CD25+FOXP3+ regulatory T cells in the pancreatic ductal adenocarcinoma microenvironment by inhibiting IL-6 secretion. Cancer Med 2024;13(17):e70110. doi: 10.1002/cam4.70110
  101. Shu Y., He L., Gao M. et al. EOGT Correlated with immune infiltration: a candidate prognostic biomarker for hepatocellular carcinoma. Front Immunol 2022;12:780509. doi: 10.3389/fimmu.2021.780509
  102. Li J., Zhang X., Liu B. et al. The expression landscape of FOXP3 and its prognostic value in breast cancer. Ann Transl Med 2022;10(14):801. doi: 10.21037/atm-22-3080
  103. Xie M., Jiang Q., Zhao S. et al. Prognostic value of tissue-infiltrating immune cells in tumor microenvironment of follicular lymphoma: a meta-analysis. Int Immunopharmacol 2020;85:106684. doi: 10.1016/j.intimp.2020.106684
  104. Kelley T.W., Parker C.J. CD4 (+)CD25 (+)Foxp3 (+) regulatory T cells and hematologic malignancies. Front Biosci (Schol Ed) 2010;2(3):980–92. doi: 10.2741/s114
  105. Li H., Zhang M.J., Zhang B. et al. Mature tertiary lymphoid structures evoke intra-tumoral T and B cell responses via progenitor exhausted CD4+ T cells in head and neck cancer. Nat Commun 2025;16(1):4228. doi: 10.1038/s41467-025-59341-w
  106. McCoy M.J., Hemmings C., Miller T.J. et al. Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer. Br J Cancer 2015;113(12):1677–86. doi: 10.1038/bjc.2015.427
  107. Westdorp H., Fennemann F.L., Weren R.D. et al. Opportunities for immunotherapy in microsatellite instable colorectal cancer. Cancer Immunol Immunother 2016;65(10):1249–59. doi: 10.1007/s00262-016-1832-7
  108. Dylag-Trojanowska K., Rogala J., Pach R. et al. T Regulatory CD4+CD25+FoxP3+ lymphocytes in the peripheral blood of left-sided colorectal cancer patients. Medicina (Kaunas) 2019;55(6):307. doi: 10.3390/medicina55060307
  109. Baßler K., Schmidleithner L., Shakiba M.H. et al. Identification of the novel FOXP3-dependent Treg cell transcription factor MEOX1 by high-dimensional analysis of human CD4+ T cells. Front Immunol 2023;14:1107397. doi: 10.3389/fimmu.2023.1107397
  110. Miyara M., Chader D., Sage E. et al. Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans. Proc Natl Acad Sci USA 2015;112(23):7225–30. doi: 10.1073/pnas.1508224112
  111. Lin Y., Li J., Liang S. et al. Pan-cancer analysis reveals m6A variation and cell-specific regulatory network in different cancer types. Genomics Proteomics Bioinformatics 2024;22(4):qzae052. doi: 10.1093/gpbjnl/qzae052
  112. Banik G., Betts C.B., Liudahl S.M. et al. High-dimensional multiplexed immunohistochemical characterization of immune contexture in human cancers. Methods Enzymol 2020;635:1–20. doi: 10.1016/bs.mie.2019.05.039
  113. Blattner-Johnson M., Jones D.T.W., Pfaff E. Precision medicine in pediatric solid cancers. Semin Cancer Biol 2022;84:214–27. doi: 10.1016/j.semcancer.2021.06.008
  114. Ma X., Liu Y., Liu Y. et al. Pan-Cancer Genome and Transcriptome Analyses of 1,699 Paediatric Leukaemias and Solid Tumours. Nature 2018;555(7696):371–6. doi: 10.1038/nature25795
  115. Plant A.S., Koyama S., Sinai C. et al. Immunophenotyping of pediatric brain tumors: correlating immune infiltrate with histology, mutational load, and survival and assessing clonal T cell response. J Neurooncol 2018;137(2):269–78. doi: 10.1007/s11060-017-2737-9
  116. Rozowsky J.S., Meesters-Ensing J.I., Lammers J.A.S. et al. A toolkit for profiling the immune landscape of pediatric central nervous system malignancies. Front Immunol 2022;13:864423. doi: 10.3389/fimmu.2022.864423
  117. Li Y., Xu S., Xu D. et al. Pediatric pan-central nervous system tumor methylome analyses reveal immune-related lncRNAs. Front Immunol 2022;13:853904. doi: 10.3389/fimmu.2022.853904
  118. Griesinger A.M., Birks D.K., Donson A.M. et al. Characterization of distinct immunophenotypes across pediatric brain tumor types. J Immunol 2013;191(9):4880–8. doi: 10.4049/jimmunol.1301966
  119. Terry R.L., Meyran D., Ziegler D.S. et al. Immune profiling of pediatric solid tumors. J Clin Investig 2020;130(7):3391–402. doi: 10.1172/JCI137181
  120. Sherif S., Roelands J., Mifsud W. et al. The immune landscape of solid pediatric tumors. J Exp Clin Cancer Res 2022;41(1):199. doi: 10.1186/s13046-022-02397-z
  121. Kushner B.H., Cheung I.Y., Modak S. et al. Phase I trial of a bivalent gangliosides vaccine in combination with β-glucan for high-risk neuroblastoma in second or later remission. Clin Cancer Res 2014;20(5):1375–82. doi: 10.1158/1078-0432.CCR-13-1012
  122. Durfee R.A., Mohammed M., Luu H.H. Review of osteosarcoma and current management. Rheumatol Ther 2016;3(2):221–43. doi: 10.1007/s40744-016-0046-y
  123. Bergsma F.J., Koster J., Baalman B. et al. The immune landscape of pediatric (extra)cranial solid tumors: A systematic review and integration of immunohistochemistry and single-cell RNA sequencing data. Eur J Cancer 2025;228:115708. doi: 10.1016/j.ejca.2025.115708
  124. Stahl D., Gentles A.J., Thiele R., Gütgemann I. Prognostic profiling of the immune cell microenvironment in Ewing’s sarcoma family of tumors. Oncoimmunology 2019;8(12):e1674113. doi: 10.1080/2162402X.2019.1674113
  125. Hingorani P., Maas M.L., Gustafson M.P. et al. Increased CTLA-4(+) T cells and an increased ratio of monocytes with loss of class II (CD14(+) HLA-DR(Lo/Neg)) found in aggressive pediatric sarcoma patients. J Immunother Cancer 2015;3:35. doi: 10.1186/s40425-015-0082-0
  126. Hont A.B., Dumont B., Sutton K.S. et al. The Tumor microenvironment and immune targeting therapy in pediatric renal tumors. Pediatr Blood Cancer 2022;70(2):e30110. doi: 10.1002/pbc.30110
  127. Palmisani F., Kovar H., Kager L. et al. Systematic review of the immunological landscape of wilms tumors. Mol Ther Oncolytics 2021;22:454–67. doi: 10.1016/j.omto.2021.06.016
  128. Tian K., Wang X., Wu Y. et al. Relationship of tumour-associated macrophages with poor prognosis in Wilms’ tumour. J Pediatr Urol 2020;1693):376.e1–8. doi: 10.1016/j.jpurol.2020.03.016
  129. Fiore P.F., Vacca P., Tumino N. et al. Wilms’ tumor primary cells display potent immunoregulatory properties on NK cells and macrophages. Cancers (Basel) 2021;13(2):224. doi: 10.3390/cancers13020224
  130. Sarver A.L., Xie C., Riddle M.J. et al. Retinoblastoma tumor cell proliferation is negatively associated with an immune gene expression signature and increased immune cells. Lab Investig J Tech Methods Pathol 2021;101(6):701–18. doi: 10.1038/s41374-021-00573-x
  131. Byroju V.V., Nadukkandy A.S., Cordani M., Kumar L.D. Retinoblastoma: present scenario and future challenges. Cell Commun Signal 2023;21(1):226. doi: 10.1186/s12964-023-01223-z
  132. Mao P., Shen Y., Xu X., Zhong J. Comprehensive analysis of the immune cell infiltration landscape and immune-related methylation in retinoblastoma. Front Genet 2022;13:864473. doi: 10.3389/fgene.2022.864473
  133. Wu C., Yang J., Xiao W. et al. Single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma. Cell Death Dis 2022;13(5):438. doi: 10.1038/s41419-022-04904-8
  134. Miracco C., Toti P., Gelmi M.C. et al. Retinoblastoma is characterized by a cold, CD8+ cell poor, PD-L1-microenvironment, which turns into hot, CD8+ Cell Rich, PD-L1+ after chemotherapy. Investig Ophthalmol Vis Sci 2021;62(2):6. doi: 10.1167/iovs.62.2.6
  135. Guo J.-J., Ye Y.-Q., Liu Y.-D. et al. Interaction between human leukocyte antigen (HLA-C) and killer cell ig-like receptors (KIR2DL) inhibits the cytotoxicity of natural killer cells in patients with hepatoblastoma. Front Med 2022;9:947729. doi: 10.3389/fmed.2022.947729
  136. Xie F., Zhang L., Yao Q. et al. TUG1 promoted tumor progression by sponging miR-335-5p and regulating CXCR4-mediated infiltration of pro-tumor immunocytes in CTNNB1-mutated hepatoblastoma. OncoTargets Ther 2020;13:3105–15. doi: 10.2147/OTT.S234819
  137. Zhang Y., Zhang T., Yin Q., Luo H. Development and validation of genomic and epigenomic signatures associated with tumor immune microenvironment in hepatoblastoma. BMC Cancer 2021;21(1):1156. doi: 10.1186/s12885-021-08893-3
  138. Sadeghi Rad H., Monkman J., Warkiani M.E. et al. Understanding the tumor microenvironment for effective immunotherapy. Med Res Rev 2021;41(3):1474–98. doi: 10.1002/med.21765
  139. Fedorova L., Mudry P., Pilatova K. et al. Assessment of immune response following dendritic cell-based immunotherapy in pediatric patients with relapsing sarcoma. Front Oncol 2019;9:1169. doi: 10.3389/fonc.2019.01169
  140. Almeida J.S., Casanova J.M., Santos-Rosa M. et al. Natural killer T-like cells: immunobiology and role in disease. Int J Mol Sci 2023;24(3):2743. doi: 10.3390/ijms24032743
  141. Hu Y., Hu Q., Li Y. et al. γδ T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Ther 2023;8(1):434. doi: 10.1038/s41392-023-01653-8
  142. Cibulka M., Selingerova I., Fedorova L., Zdrazilova-Dubska L.Immunological aspects in oncology – circulating γδ T-cells. Klin Onkol 2015;28(2):2S60–8. (In Czech). doi: 10.14735/amko20152s60
  143. Chen X., Ghanizada M., Mallajosyula V. et al. Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses. Nat Immunol 2025;26(2):230–9. doi: 10.1038/s41590-024-02062-x
  144. Pilatova K., Budinska E., Benscikova B. et al. Circulating myeloid suppressor cells and their role in tumour immunology. Klin Onkol 2017;30(1):s166–9. (In Czech).
  145. Sieminska I., Rutkowska-Zapala M., Bukowska-Strakova K. et al. The level of myeloid-derived suppressor cells positively correlates with regulatory T cells in the blood of children with transient hypogammaglobulinaemia of infancy. Cent Eur J Immunol 2018;43(4):413–20. doi: 10.5114/ceji.2018.81359
  146. Adan A., Alizada G., Kiraz Y. et al. Flow cytometry: basic principles and applications. Crit Rev Biotechnol 2017;37(2):163–76. doi: 10.3109/07388551.2015.1128876
  147. Chu P., Weiss L. Modern immunohistochemistry. Cambridge University Press, 2016. 699 p.
  148. Niu J., Li M., Wang Y. Cell proliferation and cytotoxicity assays, the fundamentals for drug discovery. Int J Drug Disc Pharmacol 2024;3(3):100013. doi: 10.53941/ijddp.2024.100013
  149. Tabatabaei M.S., Ahmed M. Enzyme-linked immunosorbent assay (ELISA). Methods Mol Biol 2022;2508:115–34. doi: 10.1007/978-1-0716-2376-3_10
  150. Ji N., Forsthuber T.G. ELISPOT techniques. In: Multiple Sclerosis. Methods in Molecular Biology. Ed. by R. Weissert. Vol. 1304. NY: Humana Press., 2014.
  151. Hirayama D., Iida T., Nakase H. The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int J Mol Sci 2017;19(1):92. doi: 10.3390/ijms19010092

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2026 Kulyova S.A., Savelieva O.E., Baldueva I.A., Borokshinova K.M., Mikhaylova E.A., Nekhaeva T.L., Kulyova A.A., Senchurov E.M.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-57560 от  08.04.2014.