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The immune system plays a significant role in urothelial bladder cancer (UBC) progression, with CD8 +  T cells being capable to directly kill tumor cells using perforin and granzymes. However, tumors avoid immune recognition by escape mechanisms. In this study, we aim to demonstrate tumor immune escape mechanisms that suppress CD8 +  T cells cytotoxicity. 42 patients diagnosed with UBC were recruited. CD8 +  T cells from peripheral blood (PB), sentinel nodes (SN), and tumor were analyzed in steady state and  in vitro -stimulated conditions by flow cytometry, RT-qPCR, and ELISA. Mass spectrometry (MS) was used for identification of proteins from UBC cell line culture supernatants. Perforin was surprisingly found to be low in CD8 +  T cells from SN, marked by 1.8-fold decrease of  PRF1  expression, with maintained expression of granzyme B. The majority of perforin-deficient CD8 +  T cells are effector memory T (T EM ) cells with exhausted Tc2 cell phenotype, judged by the presence of PD-1 and GATA-3. Consequently, perforin-deficient CD8 +  T cells from SN are low in T-bet expression. Supernatant from muscle invasive UBC induces perforin deficiency, a mechanism identified by MS where ICAM-1 and TGFβ2 signaling were causatively validated to decrease perforin expression  in vitro . Thus, we demonstrate a novel tumor escape suppressing perforin expression in CD8 +  T cells mediated by ICAM-1 and TGFβ2, which can be targeted in combination for cancer immunotherapy.

Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFβ2 mediated pathway