Basic Research - Cancer(구연) Oral Session 3 / Basic Research - Cancer (Ⅱ) (O-026) Rm.201 10월 30일(수) 14:00-15:00 Immune exhaustion status of CD8+ tumor-infiltrating lymphocytes in urothelial bladder cancer 충북대학교 의과대학 비뇨의학교실, ¹충북대학교 의과대학 내과학교실 윤석중, 한혜숙,¹ 김희경,¹ 서성필, 강호원, 김원태, 김용준, 이상철, 김원재 Background: Immune checkpoint inhibitors (ICIs), which reinvigorate exhausted T-cells, have been approved for the systemic treatment of urothelial bladder cancer (UBC). However, only a fraction of UBC patients are responsive to ICIs and our understanding of the immune phenotype of tumor-infiltrating lymphocytes (TILs) in UBC is also limited. Therefore, we investigated immune exhaustion profiles of CD8+ TILs isolated from UBC. Methods: We obtained fresh tumor tissues and paired peripheral blood samples from 30 UBC patients who underwent transurethral resection of bladder tumor from January through July, 2019. We examined the expression of immune checkpoint receptors (PD-1, TIM-3, LAG-3, and TIGIT) of CD8+ TILs and peripheral blood CD8+ T cells using flow cytometry. Results: Among the 30 patients, 24 (80%) were nonmuscle invasive bladder cancer and the remaining 6 (20%) were muscle invasive bladder cancer. CD8+ TILs exhibited significantly higher percentages of PD-1+ (P < 0.001), TIM-3+ (P = 0.001), PD-1+TIM-3+ (P < 0.001), PD-1+LAG-3+ (P < 0.001), and PD-1+TIGIT+ (P < 0.001) cells compared to paired peripheral blood CD8+ T cells. PD-1+CD8+ TILs showed higher coexpresssion of TIM-3+ (P < 0.001), LAG-3+ (P = 0.039), and TIGIT+ (P < 0.001) than PD-1-CD8+ TILs. Additionally, among the memory CD8+ TILs, excluding CD45RA+CCR7+ naïve cells, exhibited significantly higher percentages of PD-1+ (P < 0.001), TIM-3+ (P = 0.004), LAG-3+ (P = 0.045), TIGIT+ (P = 0.037), PD-1+TIM-3+ (P = 0.004), PD-1+LAG-3+ (P = 0.041), and PD-1+TIGIT+ (P < 0.0001) cells compared to paired peripheral blood CD8+ T cells. The percentage of tumor-antigen specific CD8+ T cells expressing CD103+CD39+ was significantly higher among CD8+ TILs than peripheral blood CD8+ T cells (P = 0.003). Moreover, CD103+CD39+CD8+ TILs exhibited significantly higher percentages of PD-1+ (P < 0.001), TIM-3+ (P < 0.001), PD-1+TIM-3+ (P < 0.001), and PD-1+TIGIT+ (P = 0.001) cells compared to peripheral blood CD8+ cells. Conclusions: CD8+ TILs and peripheral blood CD8+ T cells in UBC patients exhibit disparate immune exhaustion profiles, with severe exhausted immune phenotypes present in CD8+ TILs. Further analysis is required to investigate the heterogeneous differentiation status of exhausted CD8+ TILs in UBC and their reinvigoration upon ICI treatment. keywords : bladder cancer, CD8+ T cell, tumor-infiltrating lymphocytes