Immunogenicity of recurrent mutations in MYD88 and EZH2 in non-Hodgkin lymphomas

Abstract

A fundamental challenge in cancer genomics is to design effective, personalized treatments based on the mutational profiles of tumors. Pharmacological targeting of the numerous aberrant pathways found in individual tumors remains exceedingly challenging, but T cellbased therapies are an attractive alternative because of the enormous diversity and exquisite specificity of antigen recognition. We assessed the immunogenicity of three common driver mutations in human lymphoma -MYD88 L265P , EZH2 Y641N , and EZH2 Y641Fto evaluate their suitability as targets for immunotherapy. Antigen presenting cells were loaded with overlapping peptide libraries containing each mutation and used to stimulate autologous T cells from healthy donors and lymphoma patients. Stimulated T cells were screened by interferongamma ELISPOT for reactivity to mutant versus wildtype peptides as well as full-length proteins. All three peptide libraries elicited T cell responses from multiple donors representing diverse HLA haplotypes. Moreover, we identified peptides from MYD88 L265P and EZH2 Y641N that were naturally processed and presented, and the corresponding T cell responses were specific for mutant proteins. Thus, MYD88 L265P and EZH2 Y641N both represent compelling antigens for immunotherapy of lymphoma patients.