Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses.

ABSTRACT

Our previous researches have identified immunoevasive subtype muscle-invasive bladder cancer (MIBC) characterized with immune cells infiltration patterns. Our study explored the clinical significance, immunoregulatory role and therapeutic value of intratumoral IL22-producing cells in MIBC. Two hundred and fifty-nine formalin-fixed paraffin-embedded MIBC samples and 83 freshly resected MIBC tissues and 391 TCGA MIBC samples were retrospectively evaluated. Immunohistochemistry and flow cytometry were applied to identify immune cell infiltration and functional status. In vitro intervention studies were to test the therapeutic and predictive potential of IL22+ cells. Our data revealed patients with high IL22+ cells infiltration suffered poor overall survival and recurrence-free survival in both training and validation cohorts. Only pT2 patients of combined cohort with low IL22+ cells infiltration gained survival benefits from adjuvant chemotherapy (ACT) significantly. Besides, immune contexture featured with increased pro-tumor cells and immunosuppressive cytokines was identified in patients with high IL22+ cells density. The expression pattern of exhausted and effector markers in CD8+ T cells from high IL22+ cells subgroup indicated their dysfunctional status. Importantly, nivolumab showed tumor-killing efficacy in tumors with high IL22+ cells infiltration, and immunosuppressive contexture with CD8+ T cells exhaustion was abrogated in tumors treated with anti-IL22 antibody. In summary, IL22+ cells infiltration determined immunosuppressive contexture with CD8+ T cell dysfunction. Tumor-infiltrating IL22+ cells could be used as an independent marker to predict prognosis and ACT responses. IL22+ cells infiltration possessed the potential to be a favorable predictor for nivolumab application and IL22 blockade could be a novel therapeutic strategy in MIBC.