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

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CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells
Immunity ( IF 32.4 ) Pub Date : 2020-10-13 , DOI: 10.1016/j.immuni.2020.09.010
Matthias Braun ₁ , Amelia Roman Aguilera ₂ , Ashmitha Sundarrajan ₃ , Dillon Corvino ₃ , Kimberley Stannard ₁ , Sophie Krumeich ₃ , Indrajit Das ₂ , Luize G Lima ₄ , Lizeth G Meza Guzman ₅ , Kunlun Li ₅ , Rui Li ₆ , Nazhifah Salim ₃ , Maria Villancanas Jorge ₃ , Sunyoung Ham ₄ , Gabrielle Kelly ₂ , Frank Vari ₂ , Ailin Lepletier ₂ , Ashwini Raghavendra ₂ , Sally Pearson ₂ , Jason Madore ₂ , Sebastien Jacquelin ₇ , Maike Effern ₈ , Brodie Quine ₁ , Lambros T Koufariotis ₉ , Mika Casey ₂ , Kyohei Nakamura ₂ , Eun Y Seo ₁₀ , Michael Hölzel ₁₁ , Matthias Geyer ₁₂ , Glen Kristiansen ₁₃ , Touraj Taheri ₁₄ , Elizabeth Ahern ₁₅ , Brett G M Hughes ₁₆ , James S Wilmott ₁₇ , Georgina V Long ₁₈ , Richard A Scolyer ₁₉ , Martin D Batstone ₁₆ , Jennifer Landsberg ₂₀ , Dimo Dietrich ₂₁ , Oltin T Pop ₂₂ , Lukas Flatz ₂₃ , William C Dougall ₂ , André Veillette ₂₄ , Sandra E Nicholson ₅ , Andreas Möller ₄ , Robert J Johnston ₁₀ , Ludovic Martinet ₂₅ , Mark J Smyth ₂ , Tobias Bald ₃

Affiliation

Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, McGill University, Montréal, QC, Canada.
Gordon and Jessie Gilmour Leukemia Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany; Department of Microbiology & Immunology, The University of Melbourne at the Peter Doherty Institute for Infection & Immunity, Melbourne, VIC, Australia.
Medical Genomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA.
Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
Institute of Structural Biology, University Hospital Bonn, University of Bonn, Bonn, Germany.
Institute of Pathology, University Hospital Bonn, University of Bonn, Bonn, Germany.
Pathology Queensland, Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia.
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia.
Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia.
Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; The University of Sydney, Central Clinical School, Sydney, NSW, Australia.
Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; The University of Sydney, Central Clinical School, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia.
Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia.
Department of Dermatology and Allergy, University Hospital Bonn, University of Bonn, Bonn, Germany.
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, University of Bonn, Bonn, Germany.
Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland.
Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland; Department of Dermatology, Kantonsspital St.Gallen, St.Gallen, Switzerland.
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, McGill University, Montréal, QC, Canada; Department of Medicine, University of Montréal, Montréal, QC, Canada.
Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse F-31000, France.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8⁺ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226^hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226⁺CD8⁺ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.

中文翻译：

肿瘤细胞上的 CD155 通过诱导 CD8+ T 细胞中活化受体 CD226 的降解来驱动对免疫疗法的抗性

激活受体 CD226 在淋巴细胞、单核细胞和血小板上表达，并在临床前模型中促进抗肿瘤免疫。在这里，我们检查了 CD226 在肿瘤浸润淋巴细胞 (TIL) 功能和免疫治疗抗性中的作用。在小鼠肿瘤中，大部分 CD8 ⁺ TILs 的 CD226 表面表达降低并表现出功能障碍的特征，而 CD226 ^hiTIL 功能强大。这种相关性也见于从 HNSCC 患者分离的 TIL。CD226 酪氨酸 319 (Y319) 的突变导致 CD226 表面表达增加、抗肿瘤免疫增强和免疫检查点阻断 (ICB) 疗效提高。从机制上讲，肿瘤来源的 CD155（CD226 的配体）启动了 Src 激酶对 Y319 的磷酸化，从而使 CD226 能够被 CBL-B 泛素化、内化和蛋白酶体降解。在黑色素瘤患者的治疗前样本中，CD226 ⁺ CD8 ⁺ T 细胞与 ICB 后无进展生存期的改善相关。我们的研究结果支持开发旨在维持 CD226 表达的疗法。

更新日期：2020-10-13

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