MHC class II限制性抗原呈现对于预防脑肿瘤中血液源性髓样细胞对细胞毒性T细胞的功能失调是必要的。
MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors.
发表日期：2023 Feb 13
作者：
Michael Kilian, Ron Sheinin, Chin Leng Tan, Mirco Friedrich, Christopher Krämer, Ayelet Kaminitz, Khwab Sanghvi, Katharina Lindner, Yu-Chan Chih, Frederik Cichon, Benjamin Richter, Stefanie Jung, Kristine Jähne, Miriam Ratliff, Robert M Prins, Nima Etminan, Andreas von Deimling, Wolfgang Wick, Asaf Madi, Lukas Bunse, Michael Platten
来源：
CANCER CELL
摘要：
癌症免疫疗法在细胞毒性和辅助T细胞响应的健康程度上起到了至关重要的作用。肿瘤微环境中细胞毒性T细胞无效状态是免疫疗法抵抗的主要原因。肿瘤内髓系细胞，特别是血液来源性髓系细胞，是T细胞在肿瘤微环境中失效的主要驱动因素。我们在这里展示了，基于bbm的MHCII限制性抗原呈递对于控制脑肿瘤的生长是必不可少的。bbm上的MHCII丧失会通过提高染色质可及性和Tox的表达，导致细胞内肿瘤反应性CD8+ T细胞状态的失效。机械上，CD4+ T细胞的MHCII依赖性激活限制了髓系来源性OPN，从而触发T细胞NFAT2的慢性激活。总之，我们提供证据表明，基于bbm的MHCII限制性抗原呈递是在脑肿瘤中维持功能性细胞毒性T细胞状态的关键机制。版权所有©2022 Elsevier Inc.。保留所有权利。
Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional 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 activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of NFAT2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.Copyright © 2022 Elsevier Inc. All rights reserved.