Renal cell carcinoma (RCC) is a common malignancy frequently diagnosed at the metastatic stage. We performed a comprehensive analysis of the tumor immune microenvironment (TIME) in RCC patients, including the peritumoral tissue microenvironment, to characterize the phenotypic patterns and functional characteristics of infiltrating immune cells. T cells from various compartments (peripheral blood, tumor, peritumoral area, and adjacent healthy renal tissue) were assessed using flow cytometry and Luminex analyses, both before and after T cell-specific stimulation, to evaluate activation status and migratory potential. Our findings demonstrated that tumor-infiltrating lymphocytes (TILs) exhibited heightened cytokine production compared to peritumoral T cells (pTILs), acting as the primary source of cytotoxic markers (IFN-γ, granzyme B, and FasL). CD8+ T cells primarily employed Fas Ligand for cytotoxicity, while CD4+ T cells relied on CD107a. In addition, a statistically significant negative correlation between patient mortality and the presence of CD4+CD107+ pTILs was demonstrated. The engagement with the PD-1/PD-L1 pathway was also more evident in CD4+ and CD8+ pTILs as opposed to TILs. PD-L1 expression in the non-leukocyte fraction of the tumor tissue was relatively lower than in their leukocytic counterparts and upon stimulation, peripheral blood T cells displayed much stronger responses to stimulation than TILs and pTILs. Our results suggest that tumor and peritumoral T cells exhibit limited responsiveness to additional activation signals, while peripheral T cells retain their capacity to respond to stimulatory signals.

Chemokine Research Group Institute of Infection Immunity and Inflammation College of Medical Veterinary and Life Sciences University of Glasgow Glasgow G12 8TT UK

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Immunology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Methodology Faculty of Physical Education and Sport Charles University Prague Czech Republic

Department of Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Gynecologic Oncology Centre 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Lausanne Center for Immuno oncology Toxicities Service of Immunology and Allergy Department of Medicine Lausanne University Hospital University of Lausanne Lausanne Switzerland

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Hsieh J.J., Purdue M.P., Signoretti S., Swanton C., Albiges L., Schmidinger M., et al. Renal cell carcinoma. Nat. Rev. Disease Primers. 2017;3:17009. PubMed PMC

Albiges L., Molinie V., Escudier B. Non-clear cell renal cell carcinoma: does the mammalian target of rapamycin represent a rational therapeutic target? Oncologist. 2012;17(8):1051–1062. PubMed PMC

Motzer R.J., Escudier B., McDermott D.F., George S., Hammers H.J., Srinivas S., et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. New Engl. J. Med. 2015;373(19):1803–1813. PubMed PMC

Tran J., Ornstein M.C. Clinical review on the management of metastatic renal cell carcinoma. JCO. Oncol. Practice. 2022;18(3):187–196. PubMed

Rini B.I., Plimack E.R., Stus V., Gafanov R., Hawkins R., Nosov D., et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 2019;380(12):1116–1127. PubMed

Motzer R.J., Penkov K., Haanen J., Rini B., Albiges L., Campbell M.T., et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 2019;380(12):1103–1115. PubMed PMC

Motzer R.J., Tannir N.M., McDermott D.F., Arén Frontera O., Melichar B., Choueiri T.K., et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 2018;378(14):1277–1290. PubMed PMC

Choueiri T.K., Powles T., Burotto M., Escudier B., Bourlon M.T., Zurawski B., et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 2021;384(9):829–841. PubMed PMC

Tran J., Ornstein M.C. Clinical review on the management of metastatic renal cell carcinoma. JCO. Oncol. Pract. 2022;18(3):187–196. PubMed

Bagchi S., Yuan R., Engleman E.G. Immune Checkpoint Inhibitors for the Treatment of Cancer: clinical Impact and Mechanisms of Response and Resistance. Annual Rev. Pathol.:. Mechan. Disease. 2021;16(1):223–249. PubMed

Chen M.Y., Zeng Y.C. Pseudoprogression in lung cancer patients treated with immunotherapy. Crit. Rev. Oncol. Hematol. 2022;169 PubMed

Taleb B.A. Tumour flare reaction in cancer treatments: a comprehensive literature review. Antican. Drugs. 2019;30(9):953–958. PubMed PMC

McGrail D.J., Pilié P.G., Rashid N.U., Voorwerk L., Slagter M., Kok M., et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Annal. Oncol. 2021;32(5):661–672. PubMed PMC

Fridman W.H., Galon J., Pagès F., Tartour E., Sautès-Fridman C., Kroemer G. Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res. 2011;71(17):5601–5605. PubMed

Sorbye S.W., Kilvaer T.K., Valkov A., Donnem T., Smeland E., Al-Shibli K., et al. Prognostic impact of peritumoral lymphocyte infiltration in soft tissue sarcomas. BMC. Clin. Pathol. 2012;12:5. PubMed PMC

Strizova Z., Taborska P., Stakheev D., Partlová S., Havlova K., Vesely S., et al. NK and T cells with a cytotoxic/migratory phenotype accumulate in peritumoral tissue of patients with clear cell renal carcinoma. Urol. Oncol. 2019;37(7):503–509. PubMed

Sabbatino F., Scognamiglio G., Liguori L., Marra A., Anniciello A.M., Polcaro G., et al. Peritumoral immune infiltrate as a prognostic biomarker in thin melanoma. Front. Immunol. 2020;11 PubMed PMC

Keun Park C., Kyum Kim S. Clinicopathological significance of intratumoral and peritumoral lymphocytes and lymphocyte score based on the histologic subtypes of cutaneous melanoma. Oncotarget. 2017;8(9) PubMed PMC

Fridman W.H., Galon J., Pagès F., Tartour E., Sautès-Fridman C., Kroemer G. Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res. 2011;71(17):5601–5605. PubMed

Brück O., Lee M.H., Turkki R., Uski I., Penttilä P., Paavolainen L., et al. Spatial immunoprofiling of the intratumoral and peritumoral tissue of renal cell carcinoma patients. Modern. Pathol. 2021;34(12):2229–2241. PubMed PMC

Braun D.A., Hou Y., Bakouny Z., Ficial M., Sant’ Angelo M., Forman J., et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat. Med. 2020;26(6):909–918. PubMed PMC

Gorchs L., Fernández Moro C., Bankhead P., Kern K.P., Sadeak I., Meng Q., et al. Human pancreatic carcinoma-associated fibroblasts promote expression of co-inhibitory markers on CD4(+) and CD8(+) T-cells. Front. Immunol. 2019;10:847. PubMed PMC

Harryvan T.J., Verdegaal E.M.E., Hardwick J.C.H., Hawinkels L., van der Burg S.H. Targeting of the cancer-associated fibroblast-T-cell axis in solid malignancies. J. Clin. Med. 2019;8(11) PubMed PMC

Kinoshita T., Ishii G., Hiraoka N., Hirayama S., Yamauchi C., Aokage K., et al. Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma. Cancer. Sci. 2013;104(4):409–415. PubMed PMC

Salmon H., Franciszkiewicz K., Damotte D., Dieu-Nosjean M.C., Validire P., Trautmann A., et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 2012;122(3):899–910. PubMed PMC

Sahai E., Astsaturov I., Cukierman E., DeNardo D.G., Egeblad M., Evans R.M., et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer. 2020;20(3):174–186. PubMed PMC

Liu T., Han C., Wang S., Fang P., Ma Z., Xu L., et al. Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J. Hematol. Oncol. 2019;12(1):86. PubMed PMC

Newman D.K., Fu G., Adams T., Cui W., Arumugam V., Bluemn T., et al. The adhesion molecule PECAM-1 enhances the TGF-β–mediated inhibition of T cell function. Sci. Signal. 2016;9(418):ra27–rara. PubMed PMC

Ross E.A., Coughlan R.E., Flores-Langarica A., Bobat S., Marshall J.L., Hussain K., et al. CD31 is required on CD4+ T cells to promote T cell survival during salmonella infection. The. J. Immunol. 2011;187(4):1553–1565. PubMed PMC

O'Connell J. Fas ligand and the fate of antitumour cytotoxic T lymphocytes. Immunology. 2002;105(3):263–266. PubMed PMC

Alter G., Malenfant J.M., Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J. Immunol. Methods. 2004;294(1–2):15–22. PubMed

Zhu J., Petit P.F., Van den Eynde .BJ. Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism. Cancer Immunol., Immunother.: CII. 2019;68(5):835–847. PubMed PMC

Kuchar M., Strizova Z., Votava M., Plzak J. The relevance of Fas/Fas ligand axis in the tumor microenvironment of salivary gland adenoid cystic carcinoma. Oral. Oncol. 2019;97:135–136. PubMed

Saad M.B., Hong L., Aminu M., Vokes N.I., Chen P., Salehjahromi M., et al. Predicting benefit from immune checkpoint inhibitors in patients with non-small-cell lung cancer by CT-based ensemble deep learning: a retrospective study. Lancet Digital Heal. 2023;5(7):e404–ee20. PubMed PMC

Chen X.J., Yuan S.Q., Duan J.L., Chen Y.M., Chen S., Wang Y., et al. The value of PD-L1 expression in predicting the efficacy of anti-PD-1 or anti-PD-L1 therapy in patients with cancer: a systematic review and meta-analysis. Dis. Markers. 2020;2020 PubMed PMC

Yi M., Jiao D., Xu H., Liu Q., Zhao W., Han X., et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol. Cancer. 2018;17(1):129. PubMed PMC

Bronger H., Singer J., Windmüller C., Reuning U., Zech D., Delbridge C., et al. CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer. Br. J. Cancer. 2016;115(5):553–563. PubMed PMC

Singla N., Margulis V. Locally advanced kidney cancer: a new space for immunotherapy? Europ. Urol. Oncol. 2022;5(1):118–119. PubMed

Ma L., Cheung K.C., Kishore M., Nourshargh S., Mauro C., Marelli-Berg F.M. CD31 exhibits multiple roles in regulating T lymphocyte trafficking in vivo. J. Immunol. (Baltimore,. Md:. 1950) 2012;189(8):4104–4111. PubMed PMC

Kravtsov D.S., Erbe A.K., Sondel P.M., Rakhmilevich A.L. Roles of CD4+ T cells as mediators of antitumor immunity. Front. Immunol. 2022;13 PubMed PMC

Leclair L., Depil S. [CD4(+) T Lymphocytes: major players in antitumor immune response] Med. Sci. (Paris) 2021;37(6–7):671–673. PubMed

Li T., Wu B., Yang T., Zhang L., Jin K. The outstanding antitumor capacity of CD4+ T helper lymphocytes. Biochimica. et Biophysica. Acta (BBA). -. Rev. Cancer. 2020;1874(2) PubMed