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

Abstract

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 (TEM) 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.

ATM Mutations Benefit Bladder Cancer Patients Treated With Immune Checkpoint Inhibitors by Acting on the Tumor Immune Microenvironment

“…Hartana et al noted that large numbers of T cells and other cytotoxic cells infiltrated a tumor and that the tumor stage of patients was relatively low, suggesting the possibility of using cytotoxic cells as a new immunotherapy regimen. Additionally, bladder cancer cells may reduce the infiltration of CD8 T cells by inhibiting the ICAM-1/TGFβ2 pathway ( Hartana et al, 2018a , b ). Several studies have shown that various methods of activating the immune activity of dendritic cells in bladder cancer can induce the dendritic cells to initiate an antitumor immune response ( Xiu et al, 2018 ; Domingos-Pereira et al, 2019 ).…”

Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications

“…This chronic antigen exposure may result from the inhibition of their cytotoxic potential by tumor cells with one study showing that urothelial cancer supernatants suppressed perforin expression in CD8 T cells. This was associated with upregulation of TGFβ signaling pathways, suggesting that this is TGF-β mediated (111). Additionally, the immunosuppressive environment of the tumor with a lack of IFN-γ and IL-12 production and production of immunosuppressive cytokines by multiple immune populations can directly suppress CD8 T cell responses (2).…”

Neoadjuvant Chemotherapy Reinforces Antitumour T cell Response in Urothelial Urinary Bladder Cancer

“…The critical role of this pathway in tumor immunity is underscored by findings of mutations in the PRF1 gene to increase the susceptibility to develop various human cancers (136). In congruency, we have previously reported on tumor-induced downregulation of perforin in TME resident CD8 + T cells in patients with UBC (137).…”