Poor clinical outcomes and immunoevasive contexture in SIRPα tumor-associated macrophages enriched muscle-invasive bladder cancer patients.

Objectives: In tumor immune microenvironment, the functions of tumor-associated macrophages (TAMs), including phagocytosis and immunomodulatory, have attracted increasing attention recently. With the discovery of CD47-signal regulatory protein-α (SIRPα) as "don't eat me" signaling pathway, the role of novel subpopulation of TAMs expressing SIRPα has not been fully elucidated in a wide spectrum of solid tumors including bladder cancer. In this study, we investigated the prognostic and predictive implication of SIRPα TAMs regarding clinical outcomes and adjuvant chemotherapeutic benefit in muscle-invasive bladder cancer (MIBC), and preliminarily characterized the phenotypic features of SIRPα TAMs and its relationship with immune contexture.

Materials And Methods: A total of 141 histochemical MIBC samples from Zhongshan Hospital (ZS), 45 fresh tissue samples, and 391 MIBC patients from TCGA database were enrolled in this study. SIRPα TAMs was evaluated by immunohistochemical staining of CD68 and SIRPα, and flow cytometry fluorescence staining.

Results: Our results illustrated that SIRPα TAMs were enriched in MIBC specimens. Patients with high SIRPα TAMs infiltration suffered significant poor overall survival and recurrence-free survival (P = 0.0030 and P = 0.0282). SIRPα TAMs infiltration was an independent prognosticator in multivariate Cox model. Moreover, adjuvant chemotherapy (ACT) application showed significantly survival benefit in patients with low SIRPα TAMs infiltration (P = 0.0135). SIRPα TAMs with suppressive phenotype exhibited a positive correlation with immune tolerance and dysfunctional CD8 T cells in MIBC.

Conclusions: SIRPα TAMs infiltration indicated poor prognosis and ACT resistance in MIBC. Immunosuppressive SIRPα TAMs is closely related to immune evasion with exhausted T cells states, suggesting the prospect of SIRPα TAMs as a potential therapeutic target in MIBC.