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.

癌症免疫疗法，包括过继性 T 细胞转移，可能无效，因为肿瘤会进化出抗原丢失变异克隆。激活免疫系统多个分支的疗法可能会消除逃逸变异。在这里，我们证明黑色素瘤特异性 CD4 ⁺ T 细胞疗法与 OX40 共刺激或 CTLA-4 阻断相结合可以根除含有抗原逃逸变异的黑色素瘤。正如预期的那样，需要肿瘤特异性 CD4 ⁺ T 细胞对黑色素瘤抗原进行早期靶向识别。令人惊讶的是，肿瘤的完全根除依赖于中性粒细胞，部分依赖于诱导型一氧化氮合酶。为了支持这些发现，在小鼠肿瘤和接受免疫检查点阻断治疗的黑色素瘤患者的活检中观察到广泛的中性粒细胞激活。转录组学和流式细胞术分析揭示了治疗小鼠中存在独特的抗肿瘤中性粒细胞亚群。我们的研究结果揭示了介导初始抗肿瘤免疫反应的 T 细胞与介导肿瘤抗原丢失变体破坏的中性粒细胞之间的相互作用。