法国图卢兹-保罗·萨巴蒂耶大学Ludovic Martinet课题组近日取得一项新成果。他们发现Eomes依赖性共激活受体CD226的缺失抑制了CD8⁺ T细胞的抗肿瘤功能，并阻碍了癌症免疫疗法的功效。该研究于2020年10月13日发表在国际学术期刊《免疫》上。

研究人员探究了CD8⁺ T细胞中共激活受体CD226（DNAM-1）的功能。CD226缺失的细胞占据了健康个体外周血中部分功能失调的CD8⁺T细胞。这些细胞在受到刺激后表现出LFA-1活化降低、TCR信号传导改变和开启独特的转录程序。CD226^neg CD8⁺ T细胞通过转录调节因子Eomesodermin（Eomes）相关的抗原特异性机制积聚在多种人和小鼠来源的肿瘤中。

尽管共抑制受体的表达相似，但在没有CD226的情况下，CD8⁺肿瘤浸润淋巴细胞对抗PD-1无效。在Cd226^-/-小鼠中，免疫检查点阻断功效受到阻碍。抗CD137（4-1BB）激活剂也诱导Eomes依赖性CD226的丢失，从而限制了该治疗方法的抗肿瘤功效。因此，CD226的缺失会抑制CD8⁺ T细胞的功能并限制癌症免疫疗法的疗效。

据了解，肿瘤微环境（TME）中的CD8⁺  T细胞受到各种功能决定性信号的影响。

附：英文原文

Title: Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy

Author: Marianne Weulersse, Assia Asrir, Andrea C. Pichler, Lea Lemaitre, Matthias Braun, Nadège Carrié, Marie-Véronique Joubert, Marie Le Moine, Laura Do Souto, Guillaume Gaud, Indrajit Das, Elisa Brauns, Clara M. Scarlata, Elena Morandi, Ashmitha Sundarrajan, Marine Cuisinier, Laure Buisson, Sabrina Maheo, Sahar Kassem, Arantxa Agesta, Michal Pérès, Els Verhoeyen, Alejandra Martinez, Julien Mazieres, Loc Dupré, Thomas Gossye, Vera Pancaldi, Camille Guillerey, Maha Ayyoub, Anne S. Dejean, Abdelhadi Saoudi, Stanislas Goriely, Hervé Avet-Loiseau, Tobias Bald, Mark J. Smyth, Ludovic Martinet

Issue&Volume: 2020/10/13

Abstract: CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals thatultimately determine functional outcomes. Here, we examined the role of the co-activatingreceptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctionalCD8+ T cells present in peripheral blood of healthy individuals. These cells exhibitedreduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic programupon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specificmechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similarexpression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226.Immune checkpoint blockade efficacy was hampered in Cd226/ mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss thatlimited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.

DOI: 10.1016/j.immuni.2020.09.006

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30400-3