Tumor-associated macrophages expressing galectin-9 identify immunoevasive subtype muscle-invasive bladder cancer with poor prognosis but favorable adjuvant chemotherapeutic response.

Abstract

Purpose: Tumor-associated macrophages (TAMs) exist as heterogeneous subsets and have dichotomous roles in cancer-immune evasion. This study aims to assess the clinical effects of Galectin-9⁺ tumor-associated macrophages (Gal-9⁺TAMs) in muscle-invasive bladder cancer (MIBC).

Experimental design: We identified Gal-9⁺TAMs by immunohistochemistry (IHC) analysis of a tumor microarray (TMA) (n = 141) from the Zhongshan Hospital and by flow cytometric analysis of tumor specimens (n = 20) from the Shanghai Cancer Center. The survival benefit of platinum-based chemotherapy in this subpopulation was evaluated. The effect of the tumor-immune microenvironment with different percentages of Gal-9⁺TAMs was explored.

Results: The frequency of Gal-9⁺TAMs increased with tumor stage and grade. Gal-9⁺TAMs predicted poor overall survival (OS) and recurrence-free survival (RFS) and were better than Gal-9^-TAMs and TAMs to discriminate prognostic groups. In univariate and multivariate Cox regression analyses, patients with high percentages of Gal-9⁺TAMs showed the prominent survival benefit after receiving adjuvant chemotherapy (ACT). High Gal-9⁺TAM infiltration correlated with increasing numbers of regulatory T cells (Tregs) and mast cells and decreasing numbers of CD8⁺T and dendritic cells (DCs). Dense infiltration of Gal-9⁺TAMs was related to reduced cytotoxic molecules, enhanced immune checkpoints or immunosuppressive cytokines expressed by immune cells, as well as active proliferation of tumor cells. Additionally, the subpopulation accumulated was strongly associated with PD-1⁺TIM-3⁺CD8⁺T cells.

Conclusions: Gal-9⁺TAMs predicted OS and RFS and response to ACT in MIBC patients. High Gal-9⁺TAMs were associated with a pro-tumor immune contexture concomitant with T cell exhaustion.