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

Abstract

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: , and . 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 × 10-3 × 10 T cells per donor, we identified CD4 T cells against EFISECGEII from EZH2 (presented by HLA-DRB1*13:02) and CD8 T cells against RIPIKYKA from MYD88 (presented by HLA-B*07:02). We failed to detect RIPIKYKA-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.

MYD88 L265P Mutation in Lymphoid Malignancies

“…Based on the functional consequence of MYD88 L265P activity, several strategies have been devised to halt its oncogenic activation by targeting IRAK1/4, JAK, and, the most successful target, BTK, or by disrupting the myddosome assembly. Moreover, MYD88 L265P-containing peptides can elicit human leukocyte antigen (HLA) class I-restricted cytotoxic T-cell responses (46,47), supporting the potential for T-cell receptor (TCR)-based immunotherapy (Fig. 1D).…”

“…Furthermore, P4 B Ã 15 -specific CD8 þ T cells elicited mutant peptide-restricted cytotoxicity (46). In a separate study, Nielsen and colleagues assessed T cells from healthy donors for recognition of MYD88 L265P-containing peptides and identified CD8þ T cells against RPIPIKYKA when presented by HLA-B Ã 07:02 (47). In both cases, healthy individuals harbor T cells with specific TCRs that recognize L265P-containing neoantigens restricted by MHC, highlighting the potential of TCR recognition of MYD88 L265P-derived peptides as a novel personalized therapeutic strategy.…”

The Ways of Isolating Neoantigen-Specific T Cells

“…A previous report showed that both naïve and activated neoantigen-specific T cells could be expanded from the peripheral blood of follicular lymphoma patients by priming with peptide-pulsed DCs ( 77 ). Using the same method, neoantigen-specific T cells were successfully expanded from the peripheral blood of HLA-matched healthy donors ( 30 , 78 ). These preliminary results support the use of naïve T cells as an alternative source for ACT; however, their exceptionally low frequencies in peripheral blood and requirement for repeated stimulation pose hurdles ( 79 ).…”

Next-generation sequencing technologies accelerate advances in T-cell therapy for cancer

“…The correlation of driver mutations with tumor progression may make them better targets for therapeutic immune responses. Neoantigens derived from driver mutations have been identified in lymphoma [41,42], gastrointestinal cancer [43] and melanoma [44]. However, neoantigens are frequently passenger mutations [43,45,46].…”