Department of Urology, Xiangya Hospital, Central South University, Changsha, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
J Hematol Oncol. 2024 Nov 28;17(1):117. doi: 10.1186/s13045-024-01638-2.
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.
膀胱癌（BLCA）的免疫治疗抵抗与唾液酸结合免疫球蛋白样凝集素（Siglec15）水平升高有关。这种蛋白质在促进非炎症性肿瘤微环境（TME）中起着至关重要的作用，有利于癌症进展。我们的研究证实 Siglec15 的过表达导致 CD8 T 细胞浸润减少。这种作用是通过下调促炎细胞因子和趋化因子介导的，这反过来又加剧了 BLCA 的恶性程度。此外，Siglec15 抑制效应 T 细胞的细胞毒性，导致免疫逃逸。一项体内研究表明，Siglec15 的过表达诱导非炎症性 TME 并促进对免疫治疗的抵抗。这些发现表明 Siglec15 是 BLCA 的一个潜在治疗靶点。通过调节 TME 中的炎症和 CD8 T 细胞功能，靶向 Siglec15 可能为克服免疫治疗抵抗和改善患者预后提供一种新策略。
