Evasion of immunosurveillance by the upregulation of Siglec15 in bladder cancer

Abstract

Immunotherapy resistance in bladder cancer (BLCA) is associated with elevated levels of sialic acid-binding immunoglobulin-like lectin (Siglec15). This protein plays a crucial role in fostering a noninflammatory tumor microenvironment (TME), which is conducive to cancer progression. Our study confirmed that the overexpression of Siglec15 led to a reduction in CD8⁺ T cell infiltration. This effect was mediated by the downregulation of pro-inflammatory cytokines and chemokines, which in turn exacerbated BLCA malignancy. Furthermore, Siglec15 inhibited the cytotoxicity of effector T cell, contributing to immune evasion. An in vivo study demonstrated that Siglec15 overexpression induced a non-inflammatory TME and promoted resistance to immunotherapy. These findings highlight Siglec15 as a potential therapeutic target for BLCA. By modulating inflammation in the TME and CD8⁺ T cell function, targeting Siglec15 may offer a novel strategy for overcoming immunotherapy resistance and improving patient outcomes.

Keywords: Bladder cancer; Immunotherapy; Noninflamed tumor microenvironment; Siglec15.