肿瘤内 CXCR3 趋化因子系统的活性是抗 PD-1 治疗疗效所必需的。
Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy.
机构信息
Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
出版信息
Immunity. 2019 Jun 18;50(6):1498-1512.e5. doi: 10.1016/j.immuni.2019.04.010. Epub 2019 May 13.
Despite compelling rates of durable clinical responses to programmed cell death-1 (PD-1) blockade, advances are needed to extend these benefits to resistant tumors. We found that tumor-bearing mice deficient in the chemokine receptor CXCR3 responded poorly to anti-PD-1 treatment. CXCR3 and its ligand CXCL9 were critical for a productive CD8 T cell response in tumor-bearing mice treated with anti-PD-1 but were not required for the infiltration of CD8 T cells into tumors. The anti-PD-1-induced anti-tumor response was facilitated by CXCL9 production from intratumoral CD103 dendritic cells, suggesting that CXCR3 facilitates dendritic cell-T cell interactions within the tumor microenvironment. CXCR3 ligands in murine tumors and in plasma of melanoma patients were an indicator of clinical response to anti-PD-1, and their induction in non-responsive murine tumors promoted responsiveness to anti-PD-1. Our data suggest that the CXCR3 chemokine system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes.
尽管程序性细胞死亡蛋白-1（PD-1）阻断具有令人信服的持久临床反应率，但仍需要进一步提高这些益处，以扩展到耐药肿瘤。我们发现，缺乏趋化因子受体 CXCR3 的荷瘤小鼠对抗 PD-1 治疗反应不佳。CXCR3 及其配体 CXCL9 对于用抗 PD-1 治疗的荷瘤小鼠产生有效的 CD8 T 细胞反应至关重要，但对于 CD8 T 细胞浸润肿瘤不是必需的。CXCL9 由肿瘤内 CD103 树突状细胞产生，促进了抗 PD-1 诱导的抗肿瘤反应，提示 CXCR3 促进了肿瘤微环境中树突状细胞-T 细胞的相互作用。在小鼠肿瘤和黑色素瘤患者的血浆中，CXCR3 配体是对抗 PD-1 治疗反应的指标，在无反应性小鼠肿瘤中诱导它们可促进对 PD-1 的反应性。我们的数据表明，CXCR3 趋化因子系统是对 PD-1 阻断敏感的生物标志物，增强该趋化因子系统在肿瘤内的功能可以改善临床结局。
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