德国癌症研究中心Michael Platten，Lukas Bunse和以色列特拉维夫大学Asaf Madi团队共同合作，近期取得重要工作进展。他们研究发现MHC II类限制性抗原呈递是防止脑瘤中血源性骨髓引起的细胞毒性T细胞功能紊乱所必需的。相关研究成果2023年1月12日在线发表于《癌细胞》杂志上。

据介绍，癌症免疫治疗特别依赖于细胞毒性和辅助性T细胞反应的适应性。肿瘤微环境（TME）中功能失调的细胞毒性T细胞状态是免疫治疗耐药性产生的主要原因。肿瘤内髓细胞，特别是血源性髓细胞（bbm），是TME中T细胞功能障碍的关键驱动因素。

研究人员发现，主要组织相容性复合体II类（MHCII）限制性抗原在bbm上的呈递对于控制脑肿瘤的生长至关重要。bbm上MHCII的缺失通过增加染色质的可及性和T细胞耗竭的关键调节因子Tox的表达，来驱动功能失调的瘤内肿瘤反应性CD8⁺ T细胞状态。从机制上讲，CD4⁺ T细胞的MHCII依赖性激活限制了髓系来源的骨桥蛋白，该骨桥蛋白在肿瘤反应性CD8⁺ T细胞中触发NFAT2的慢性激活。

总之，证据表明，MHCII限制性抗原在bbm上的呈递是在脑肿瘤中直接维持功能性细胞毒性T细胞状态的关键机制。

附：英文原文

Title: MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

Author: Michael Kilian, Ron Sheinin, Chin Leng Tan, Mirco Friedrich, Christopher Krmer, Ayelet Kaminitz, Khwab Sanghvi, Katharina Lindner, Yu-Chan Chih, Frederik Cichon, Benjamin Richter, Stefanie Jung, Kristine Jhne, Miriam Ratliff, Robert M. Prins, Nima Etminan, Andreas von Deimling, Wolfgang Wick, Asaf Madi, Lukas Bunse, Michael Platten

Issue&Volume: 2023-01-12

Abstract: Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cellresponses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME)are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularlyblood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We showhere that major histocompatibility complex class II (MHCII)-restricted antigen presentationon bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drivesdysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activationof CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activationof NFAT2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentationon bbm is a key mechanism to directly maintain functional cytotoxic T cell statesin brain tumors.

DOI: 10.1016/j.ccell.2022.12.007

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00593-1