美国威尔康奈尔医学中心Taha Merghoub团队发现，T细胞免疫疗法利用中性粒细胞来消除肿瘤抗原逃逸变体。这一研究成果于2023年3月30日发表在国际学术期刊《细胞》上。
研究人员表明，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需要的。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，研究人员在小鼠肿瘤和接受免疫检查点阻断治疗的黑色素瘤患者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。
这些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。
据介绍，癌症免疫疗法，包括过继性T细胞转移，可能是无效的，因为肿瘤会演化成显示抗原丢失的变体克隆。激活免疫系统多个分支的疗法可能会消除逃逸变体。
附：英文原文
Title: T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants
Author: Daniel Hirschhorn, Sadna Budhu, Lukas Kraehenbuehl, Mathieu Gigoux, David Schrder, Andrew Chow, Jacob M. Ricca, Billel Gasmi, Olivier De Henau, Levi Mark B. Mangarin, Yanyun Li, Linda Hamadene, Anne-Laure Flamar, Hyejin Choi, Czrina A. Cortez, Cailian Liu, Aliya Holland, Sara Schad, Isabell Schulze, Allison Betof Warner, Travis J. Hollmann, Arshi Arora, Katherine S. Panageas, Gabrielle A. Rizzuto, Rebekka Duhen, Andrew D. Weinberg, Christine N. Spencer, David Ng, Xue-Yan He, Jean Albrengues, David Redmond, Mikala Egeblad, Jedd D. Wolchok, Taha Merghoub
Issue&Volume: 2023/03/30
Abstract: Cancer immunotherapies, including adoptive T cell transfer, can be ineffective becausetumors evolve to display antigen-loss-variant clones. Therapies that activate multiplebranches of the immune system may eliminate escape variants. Here, we show that melanoma-specificCD4+ T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicatemelanomas containing antigen escape variants. As expected, early on-target recognitionof melanoma antigens by tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophilsand partly dependent on inducible nitric oxide synthase. In support of these findings,extensive neutrophil activation was observed in mouse tumors and in biopsies of melanomapatients treated with immune checkpoint blockade. Transcriptomic and flow cytometryanalyses revealed a distinct anti-tumorigenic neutrophil subset present in treatedmice. Our findings uncover an interplay between T cells mediating the initial anti-tumorimmune response and neutrophils mediating the destruction of tumor antigen loss variants.
DOI: 10.1016/j.cell.2023.03.007
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00225-8