Distinct leukocyte populations and cytokine secretion profiles define tumoral and peritumoral areas in renal cell carcinoma

• Published in: Translational oncology 2024-04, Vol.42, p.101891-101891, Article 101891
• Main Authors: Borcinova, Martina, Bartolini, Robin, Foley, Lily Koumbas, Novak, Vojtech, Taborska, Pavla, Stakheev, Dmitry, Rataj, Michal, Smrz, Daniel, Fialova, Martina, Hacek, Jaromir, Komarc, Martin, Vesely, Stepan, Babjuk, Marek, Striz, Ilja, Bartunkova, Jirina, Buchler, Tomas, Ozaniak Strizova, Zuzana
• Format: Article
• Language: English
• Subjects: CAFs; CD8 T cells; cytotoxicity; Kidney cancer; kidney cancer cytokines; Original Research; PECAM-1; peritumoral tissue; RCC TME; Renal carcinoma immunotherapy; Tumor immune microenvironment; Tumor-infiltrating lymphocytes
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2024.101891

•Tumor-infiltrating lymphocytes (TILs) exhibit higher cytokine production compared to peripheral TILs (pTILs) in patients with RCC.•CD8+ T cells predominantly utilize Fas ligand, while CD4+ T cells rely on CD107a for cytotoxicity in RCC.•The migration capacity of tumor-infiltrating lymphocytes (TILs) is inversely correlated with the proportion of cancer-associated fibroblasts (CAFs).•Tumor and peritumoral T cells exhibit limited responsiveness to additional activation signals, while peripheral T cells in circulation retain their capacity to respond to stimulatory signals. 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 [Display omitted]