Abstract
CD4+ T cells specific for immunoglobulin-derived neoantigens target autologous lymphoma cells.
Major finding: CD4+ T cells specific for immunoglobulin-derived neoantigens target autologous lymphoma cells.
Approach: Tumor neoantigens were discovered using MHC isolation, peptide identification, and exome sequencing.
Impact: Immunoglobulin neoantigens may be targets for immunotherapy in patients with lymphoma.
Somatic mutations can create cancer neoantigens that distinguish them from normal cells and allow recognition by cytotoxic T cells. Identification of neoantigens has proven difficult and is often achieved by “reverse immunology” approaches relying on isolation of cognate T cells to identify candidate neoantigens. Khodadoust, Olsson, and colleagues used an integrated genomic and proteomic strategy to identify tumor antigens directly from cancer cells. MHC class I and class II ligands from 17 patients with untreated mantle-cell lymphoma (MCL), and 2 MCL cell lines were purified and analyzed by LC/MS-MS. These data were integrated with matched tumor and germline whole-exome sequencing data and targeted sequencing of lymphoma immunoglobulin (Ig). In all 17 patients, the neoantigenic peptides discovered were derived exclusively from Ig heavy-chain or light-chain variable regions. Both MHC-I and MHC-II presented the Ig heavy chain. The majority of peptides presented by MHC-I mapped to the Ig constant region, whereas the large majority of Ig peptides presented by MHC-II mapped to the variable region. Within the complementarity-determining region 3 (CDR3), nearly half of MHC-II–presented peptides were neoantigens created by somatic hypermutation or V(D)J gene rearrangement. Similarly, MHC-II presented 14 neoantigen peptides derived from light-chain variable regions formed by somatic hypermutation, whereas MHC-I did not present any. Isolated circulating patient-derived neoantigen-specific CD4+ T cells were able to mediate autologous lymphoma cell killing, whereas cells lacking the lymphoma neoantigen were unaffected. These findings demonstrate that combined genomic and proteomic analysis allows for the identification of tumor antigens, and suggest that Ig neoantigens may be therapeutic targets in lymphoma.
