胶原通过 LAIR1 依赖性 CD8 T 细胞耗竭促进癌症对 PD-1/PD-L1 的耐药性。

Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8 T cell exhaustion.

机构信息

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

出版信息

Nat Commun. 2020 Sep 9;11(1):4520. doi: 10.1038/s41467-020-18298-8.

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8 T cells and increased exhausted CD8 T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.

肿瘤细胞外基质与药物耐药性和免疫抑制有关。在这里，蛋白质组学和 RNA 分析显示，对 PD-1/PD-L1 阻断有耐药性的肺部肿瘤中胶原蛋白水平升高。此外，在小鼠和人类肺部肿瘤中，胶原水平升高与总 CD8 T 细胞减少和耗竭 CD8 T 细胞亚群增加相关。胶原诱导的 T 细胞衰竭通过受体 LAIR1 发生，LAIR1 在 CD18 与胶原相互作用后上调，并通过 SHP-1 诱导 T 细胞衰竭。通过抑制 LOXL2 减少肿瘤胶原沉积可增加 T 细胞浸润，减少耗竭 T 细胞，并消除对抗 PD-L1 的耐药性。通过过表达 LAIR2 或抑制 SHP-1 来消除 LAIR1 的免疫抑制作用，可使对 PD-1 有耐药性的肺部肿瘤对抗 PD-1 敏感。临床上，接受 PD-1 阻断治疗的黑色素瘤患者中胶原、LAIR1 和 TIM-3 的表达增加预示着生存和反应较差。我们的研究确定了胶原和 LAIR1 作为免疫治疗耐药的潜在标志物，并验证了多种有前途的治疗组合。