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... More
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.
