澳大利亚QIMR Berghofer医学研究所Tobias Bald和Mark J. Smyth团队合作取得一项新成果。他们发现在肿瘤细胞中CD155通过诱导CD8⁺ T细胞中活化受体CD226的降解来产生对免疫疗法的抵抗。2020年10月13日出版的《免疫》发表了这项成果。

研究人员探究了激活受体CD226在肿瘤浸润淋巴细胞（TILs）中的功能和其在免疫疗法抵抗中的作用。在小鼠肿瘤中，CD226在大部分CD8⁺ TILs 细胞表面表达降低，并表现出功能障碍的特点，而CD226^hi TILs的功能则很强。从HNSCC患者中分离的TIL也具有这种相关性。CD226 319酪氨酸（Y319）的突变导致CD226在细胞表面表达增加、抗肿瘤免疫增强和免疫检查点封锁（ICB）效力提高。

从机理上讲，肿瘤细胞内CD155（CD226的配体）通过Src激酶引发Y319的磷酸化，从而使CD226被CBL-B泛素化、吞噬和蛋白酶体降解。在黑素瘤患者治疗前的样品中，CD226⁺ CD8⁺ T细胞与ICB术后无进展生存期改善相关。该发现证明了维持CD226的表达在治疗中的潜在应用。

据了解，CD226在淋巴细胞、单核细胞和血小板细胞中表达，并且在临床前模型中促进抗肿瘤免疫。

附：英文原文

Title: CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells

Author: Matthias Braun, Amelia Roman Aguilera, Ashmitha Sundarrajan, Dillon Corvino, Kimberley Stannard, Sophie Krumeich, Indrajit Das, Luize G. Lima, Lizeth G. Meza Guzman, Kunlun Li, Rui Li, Nazhifah Salim, Maria Villancanas Jorge, Sunyoung Ham, Gabrielle Kelly, Frank Vari, Ailin Lepletier, Ashwini Raghavendra, Sally Pearson, Jason Madore, Sebastien Jacquelin, Maike Effern, Brodie Quine, Lambros T. Koufariotis, Mika Casey, Kyohei Nakamura, Eun Y. Seo, Michael Hlzel, Matthias Geyer, Glen Kristiansen, Touraj Taheri, Elizabeth Ahern, Brett G.M. Hughes, James S. Wilmott, Georgina V. Long, Richard A. Scolyer, Martin D. Batstone, Jennifer Landsberg, Dimo Dietrich, Oltin T. Pop, Lukas Flatz, William C. Dougall, André Veillette, Sandra E. Nicholson, Andreas Mller, Robert J. Johnston, Ludovic Martinet, Mark J. Smyth, Tobias Bald

Issue&Volume: 2020/10/13

Abstract: The activating receptor CD226 is expressed on lymphocytes, monocytes, and plateletsand promotes anti-tumor immunity in pre-clinical models. Here, we examined the roleof CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance toimmunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction,whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated fromHNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surfaceexpression, enhanced anti-tumor immunity and improved efficacy of immune checkpointblockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiatedphosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 byCBL-B, internalization, and proteasomal degradation. In pre-treatment samples frommelanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findingsargue for the development of therapies aimed at maintaining the expression of CD226.

DOI: 10.1016/j.immuni.2020.09.010

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30404-0