癌症免疫疗法，包括采用T细胞转移的治疗方法，可能无效，因为肿瘤会进化成表现出抗原丢失变异体克隆。激活多个免疫系统分支的治疗方法可能会消除逃逸变异体。在这里，我们展示了黑色素瘤特异性CD4 + T细胞疗法与OX40协同刺激或CTLA-4阻断相结合，可以根除含有抗原逃逸变异体的黑色素瘤。正如预期的，肿瘤特异性CD4 + T细胞对黑色素瘤抗原的早期目标识别是必需的。令人惊讶的是，完全的肿瘤根除取决于中性粒细胞，部分取决于诱导型一氧化氮合酶。支持这些发现，大量的中性粒细胞激活被观察到在小鼠肿瘤和在接受免疫检查点阻滞治疗的黑色素瘤患者的活检中。转录组和流式细胞术分析揭示了存在于治疗小鼠中的独特的抗肿瘤中性粒细胞亚群。我们的发现揭示了T细胞介导的初始抗肿瘤免疫应答和中性粒细胞介导肿瘤抗原丢失变异体破坏之间的相互作用。版权所有©2023 Elsevier Inc.。保留所有权利。

Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4+ T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants.Copyright © 2023 Elsevier Inc. All rights reserved.