Intratumoral CCR5+ neutrophils identify immunogenic subtype muscle-invasive bladder cancer with favorable prognosis and therapeutic responses.

Our previous studies revealed tumor-infiltrating neutrophils (TINs) played dichotomous roles in different cancers, indicating diverse TINs subtypes might orchestrate anti-tumor immunity or immune evasion, respectively. This study aimed to investigate the clinical significance and immune characteristics of CCR5⁺TINs in muscle-invasive bladder cancer (MIBC). Two hundred and fifty-seven MIBC patients from two clinical centers and 95 fresh MIBC samples were included. CCR5⁺TINs were stained by immunohistochemistry, and the relationship between patients' clinic-pathological features and prognosis was evaluated, respectively. Immunohistochemistry and flow cytometry were applied to assess the immune features of CCR5⁺TINs and their correlations with other immune cells. In vitro study was conducted to estimate immune characteristics of CCR5⁺TINs and their predictive potential for pembrolizumab therapeutic response. In the two MIBC cohorts, we found that high CCR5⁺TINs infiltration could predict better overall survival (OS, P=.032, 0.039) and recurrence-free survival (RFS, P=.001, 0.006) and be associated with survival benefit from adjuvant chemotherapy (ACT, P<.001 for OS and P=.022 for RFS, respectively) in merely pT2N0 MIBC. Maraviroc could partly reduce IFN-γ secretion by CCR5⁺TINs (P<.001). CCR5⁺TINs correlated with higher expression of effector molecules within CD8⁺T cells. Notably, pembrolizumab treatment could only elevate the apoptosis status of tumor cells in the CCR5⁺TINs high subgroup (P <.001), other than CCR5⁺TINs low subgroup (P=.481). Our results indicate that CCR5⁺TINs could prime anti-tumor immune response through autonomous IFN-γ release, thus leading to favorable prognosis and superior therapeutic response to ACT and immunotherapy in MIBC. [ABSTRACT FROM AUTHOR]