Mp55-02 ccr8 blockade primes anti-tumor immunity through intratumoral regulatory t cells destabilization in muscle-invasive bladder cancer

INTRODUCTION AND OBJECTIVE: Regulatory T cells (Tregs) play a major role in the development of an immunosuppressive tumor microenvironment. CCR8 has recently been identified as an important chemokine receptor on intratumoral Tregs and is known to be critical for CCR8+Treg-mediated immunosuppression. This study aimed to investigate the clinical significance and inherent molecular mechanisms of intratumoral CCR8+ Tregs in Muscle-invasive bladder cancer (MIBC). METHODS: 259 MIBC patients from two independent clinic centers were included in the study. 83 fresh MIBC tumor tissues were used to evaluate the proportion and function of immune cells via flow cytometry and ex vivo intervention experiments. 396 MIBC patients of TCGA were applied for bioinformatics analysis. RESULTS: We found that the CCR8 expression by intratumoral Tregs maintained the stability and potentiated their suppressive function by upregulating the expression of transcript factors Foxo1 and c-Maf. High level of CCR8+ Tregs is associated with immune tolerance and predicts poor survival and inferior therapeutic responsiveness to chemotherapy. Moreover, we revealed that CCR8 blockade using neutralizing antibody destabilized intratumoral Tregs into a fragile phenotype, reactivated the antitumor immunity and augmented the therapeutic benefits of the anti-PD-1 antibody in MIBC. CONCLUSIONS: Our study presents the mechanism of CCR8 in maintaining the stability of intratumoral Tregs in MIBC and indicates that therapeutic targeting of CCR8 could provide a more specific modulation of Tregs and augment immunotherapy in patients with MIBC.Source of Funding: This study was funded by grants from National Natural Science Foundation of China (81570607, 81671628, 31770851, 81702496, 81702497, 81702805, 81772696, 81871306, 81872082, 81902556, 81902563, 81902898, 81974393), Three-year action plan for promoting clinical skills and clinical innovation in municipal hospitals of Shanghai Shenkang (16CR2003A), National Natural Science Foundation for Young Scholars of China (81902566), Shanghai Jiaotong University Medical-Engineering Cross Research Fund (YG2019QNA53), National Key R&D Program of China (2017YFC0114303), Shanghai Municipal Natural Science Foundation (16ZR1406500, 17ZR1405100, 19ZR1431800), Guide Project of Science and Technology Commission of Shanghai Municipality (17411963100), Shanghai Sailing Program (18YF1404500, 19YF1407900, 19YF1427200), Shanghai Municipal Commission of Health and Family Planning Program (20174Y0042, 201840168, 20184Y0151), Fudan University Shanghai Cancer Center for Outstanding Youth Scholars Foundation (YJYQ201802) and Shanghai Cancer Research Charity Center. All these study sponsors have no roles in the study design, in the collection, analysis and interpretation of data.