Mapping the human T cell repertoire to recurrent driver mutations in MYD88 and EZH2 in lymphoma

• Published in: Oncoimmunology Vol. 6; no. 7; p. e1321184
• Main Authors: Nielsen, Julie S., Chang, Andrew R., Wick, Darin A., Sedgwick, Colin G., Zong, Zusheng, Mungall, Andrew J., Martin, Spencer D., Kinloch, Natalie N., Ott-Langer, Susann, Brumme, Zabrina L., Treon, Steven P., Connors, Joseph M., Gascoyne, Randy D., Webb, John R., Berry, Brian R., Morin, Ryan D., Macpherson, Nicol, Nelson, Brad H.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2017; Taylor & Francis Group
• Subjects: Driver mutation; EZH2; immunotherapy; lymphoma; MYD88; neoantigen; next-generation sequencing; Original Research; Driver mutation; neoantigen; next-generation sequencing; immunotherapy; lymphoma; MYD88; EZH2
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2017.1321184

Oncogenic "driver" mutations are theoretically attractive targets for the immunotherapy of lymphoid cancers, yet the proportion that can be recognized by T cells remains poorly defined. To address this issue without any confounding effects of the patient's immune system, we assessed T cells from 19 healthy donors for recognition of three common driver mutations in lymphoma: MYD88 L265P , EZH2 Y641F , and EZH2 Y641N . Donors collectively expressed the 10 most prevalent HLA class I alleles, including HLA-A*02:01. Peripheral blood T cells were primed with peptide-loaded dendritic cells (DC), and reactive T cells were assessed for recognition of naturally processed mutant versus wild type full-length proteins. After screening three driver mutations across 17-26 HLA class I alleles and 3 × 10 6 −3 × 10 7 T cells per donor, we identified CD4 + T cells against EFISENCGEII from EZH2 Y641N (presented by HLA-DRB1*13:02) and CD8 + T cells against RPIPIKYKA from MYD88 L265P (presented by HLA-B*07:02). We failed to detect RPIPIKYKA-specific T cells in seven other HLA-B*07:02-positive donors, including two lymphoma patients. Thus, healthy donors harbor T cells specific for common driver mutations in lymphoma. However, such responses appear to be rare due to the combined limitations of antigen processing, HLA restriction, and T cell repertoire size, highlighting the need for highly individualized approaches for selecting targets.