Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201.
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and.
J Immunol. 2018 May 1;200(9):3304-3311. doi: 10.4049/jimmunol.1701617. Epub 2018 Mar 30.
Immunotherapy is becoming the standard of care for melanoma. However, resistance to therapy is a major problem. Previously, we showed that tumor-specific, cytotoxic CD4 T cells from tyrosinase-related protein 1 transgenic mice could overcome secondary resistance to recurring melanoma when anti-programmed cell death 1 ligand (PD-L1) checkpoint blockade was combined with either anti-lymphocyte-activated gene 3 (LAG-3) Abs or depletion of tumor-specific regulatory T (T) cells. In this study, we show that PD-L1 expressed by the host, not B16 melanoma, plays a major role in the early stages of exhaustion or primary resistance. We observed durable regression of melanoma in tumor-bearing PD-L1RAG mice with transfer of naive tumor-specific CD4 T cells. However, exhausted tumor-specific CD4 T cells, which included tumor-specific T cells, failed to maintain durable regression of tumors in PD-L1RAG mice unless tumor-specific T cells were eliminated, showing nonredundant pathways of resistance to immunotherapy were present. Translating these findings to a clinically relevant model of cancer immunotherapy, we unexpectedly showed that anti-PD-L1 checkpoint blockade mildly improved immunotherapy with tumor-specific CD4 T cells and irradiation in wild-type mice. Instead, anti-LAG-3 checkpoint blockade, in combination with tumor-specific CD4 T cells and irradiation, overcame primary resistance and treated established tumors resulting in fewer recurrences. Because LAG-3 negatively regulates effector T cell function and activates T cells, LAG-3 blockade may be more beneficial in overcoming primary resistance in combination immunotherapies using adoptive cellular therapy and irradiation than blockade of PD-L1.
免疫疗法正在成为黑色素瘤的标准治疗方法。然而，对治疗的耐药性是一个主要问题。此前，我们表明，来自酪氨酸相关蛋白 1 转基因小鼠的肿瘤特异性细胞毒性 CD4 T 细胞可以克服复发性黑色素瘤的继发性耐药，当抗程序性细胞死亡 1 配体（PD-L1）检查点阻断与抗淋巴细胞激活基因 3（LAG-3）Abs 或肿瘤特异性调节性 T（T）细胞耗竭联合使用时。在这项研究中，我们表明，宿主而非 B16 黑色素瘤表达的 PD-L1 在衰竭或原发性耐药的早期阶段起着主要作用。我们观察到，在携带 PD-L1RAG 小鼠中转移幼稚的肿瘤特异性 CD4 T 细胞可导致黑色素瘤的持久消退。然而，耗尽的肿瘤特异性 CD4 T 细胞，包括肿瘤特异性 T 细胞，未能维持 PD-L1RAG 小鼠中肿瘤的持久消退，除非消除肿瘤特异性 T 细胞，表明存在非冗余的免疫治疗耐药途径。将这些发现转化为癌症免疫治疗的临床相关模型，我们出人意料地表明，抗 PD-L1 检查点阻断轻度改善了野生型小鼠中肿瘤特异性 CD4 T 细胞和放疗的免疫治疗。相反，抗 LAG-3 检查点阻断与肿瘤特异性 CD4 T 细胞和放疗联合使用，克服了原发性耐药并治疗了已建立的肿瘤，导致复发减少。由于 LAG-3 负调节效应 T 细胞功能并激活 T 细胞，因此在使用过继细胞治疗和放疗的联合免疫疗法中，LAG-3 阻断可能比 PD-L1 阻断更有利于克服原发性耐药。
