Abstract
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.
摘要
癌症免疫疗法，包括过继性T细胞疗法，可能会因为肿瘤演变为抗原丢失变异的克隆而无效。激活免疫系统多个分支的疗法可能会消除逃逸变体。在这项研究中，我们发现黑色素瘤特异性CD4+T细胞治疗与OX40共刺激或CTLA-4阻断相结合，可以根除含有抗原逃逸变体的黑色素瘤。正如预期的那样，肿瘤特异性CD4+T细胞对黑色素瘤抗原的早期靶向识别是必需的。令人惊讶的是，完全根除肿瘤依赖于中性粒细胞，部分依赖于诱导性一氧化氮合成酶。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。转录组和流式细胞仪分析显示，在接受治疗的小鼠中存在一个独特的抗肿瘤性中性粒细胞亚群。我们的发现揭示了介导初始抗肿瘤免疫反应的T细胞和介导破坏肿瘤抗原损失变体的中性粒细胞之间的相互作用。
参考文献
T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants. Cell, 186(7), 1432–1447.e17. https://doi.org/10.1016/j.cell.2023.03.007.
