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

• Main Authors: Julie S. Nielsen, Andrew R. Chang, Darin A. Wick, Colin G. Sedgwick, Zusheng Zong, Andrew J. Mungall, Spencer D. Martin, Natalie N. Kinloch, Susann Ott-Langer, Zabrina L. Brumme, Steven P. Treon, Joseph M. Connors, Randy D. Gascoyne, John R. Webb, Brian R. Berry, Ryan D. Morin, Nicol Macpherson, Brad H. Nelson
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2017-07-01
• Series: OncoImmunology
• Subjects: driver mutation; ezh2; immunotherapy; lymphoma; myd88; neoantigen; next-generation sequencing
• Online Access: http://dx.doi.org/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: MYD88L265P, EZH2Y641F, and EZH2Y641N. 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 × 106−3 × 107 T cells per donor, we identified CD4+ T cells against EFISENCGEII from EZH2Y641N (presented by HLA-DRB1*13:02) and CD8+ T cells against RPIPIKYKA from MYD88L265P (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.