TIM-3 调节乳腺癌树突状细胞的功能和对化疗的反应。
TIM-3 Regulates CD103 Dendritic Cell Function and Response to Chemotherapy in Breast Cancer.
机构信息
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA.
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA.
出版信息
Cancer Cell. 2018 Jan 8;33(1):60-74.e6. doi: 10.1016/j.ccell.2017.11.019.
Abstract
Intratumoral CD103 dendritic cells (DCs) are necessary for anti-tumor immunity. Here we evaluated the expression of immune regulators by CD103 DCs in a murine model of breast cancer and identified expression of TIM-3 as a target for therapy. Anti-TIM-3 antibody improved response to paclitaxel chemotherapy in models of triple-negative and luminal B disease, with no evidence of toxicity. Combined efficacy was CD8 T cell dependent and associated with increased granzyme B expression; however, TIM-3 expression was predominantly localized to myeloid cells in both human and murine tumors. Gene expression analysis identified upregulation of Cxcl9 within intratumoral DCs during combination therapy, and therapeutic efficacy was ablated by CXCR3 blockade, Batf3 deficiency, or Irf8 deficiency.
摘要
肿瘤内 CD103 树突状细胞 (DCs) 对于抗肿瘤免疫是必需的。在这里，我们评估了乳腺癌小鼠模型中 CD103 DCs 表达的免疫调节剂，并确定 TIM-3 的表达是治疗的靶点。抗 TIM-3 抗体改善了三阴性和管腔 B 疾病模型中紫杉醇化疗的反应，没有毒性的证据。联合疗效依赖于 CD8 T 细胞，与颗粒酶 B 表达增加有关；然而，TIM-3 表达主要局限于人类和鼠类肿瘤中的髓样细胞。基因表达分析在联合治疗期间发现肿瘤内 DC 中 Cxcl9 的上调，并且 CXCR3 阻断、Batf3 缺陷或 Irf8 缺陷消除了治疗效果。
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