MHC class II restricted neoantigens play a critical role in response to immune checkpoint therapy (ICT).

  • Major finding: MHC class II restricted neoantigens play a critical role in response to immune checkpoint therapy (ICT).

  • Concept: CD4+ helper T cells help priming, maturation, and memory development of antitumor CD8+ T cells.

  • Impact: Expression of immunogenic MHC-II neoantigens may predict sensitivity to ICT in patients with cancer.

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Immune checkpoint therapy (ICT) augments antitumor immunity but is efficacious in only a subset of patients with cancer. Therefore, identifying the determinants of successful ICT and predictors of response are needed. Although the ICT-mediated enhancement of CD8+ T-cell cytotoxicity is well established, the role of MHC class II (MHC-II) restricted CD4+ T cells in response to ICT remains less understood. Having previously identified a point mutation in laminin-α subunit 4 (mLAMA4) as an MHC-I neoantigen in T3 sarcoma cells, Alspach and colleagues developed an algorithm to predict MHC-II neoantigens and identified an N710Y somatic point mutation in integrin-β1 (mITGB1) as an MHC-II neoantigen in T3 cells. Consistent with this finding, CD4+ T3 tumor-infiltrating lymphocytes exhibited increased IFNγ production upon incubation with mITGB1 peptide as well as increased mITGB1 tetramer staining compared to control. Expression of both mLAMA4 and mITGB1 in T3 cells demonstrated that the expression of MHC-II neoantigen is important for ICT response and tumor vaccine efficacy. Similarly, expression of neoantigens in a nonimmunogenic KP9025 sarcoma mouse model revealed that sensitivity to ICT depends on a combinatorial effect of both CD4+ and CD8+ T cells in the tumor microenvironment (TME). Further, mITGB1-specific CD4+ T cells exhibited an activated Th1 phenotype and promoted both priming and maturation of CD8+ T cells. Tumor-specific expression of mITGB1 and the presence of tumor-specific CD4+ T cells and MHC-I–specific CD8+ T cells in the TME were respectively required, but insufficient, for ICT-mediated tumor rejection and inducing localized changes in tumor immune composition. Collectively, these results suggest a critical role for MHC-II neoantigens in sensitivity to ICT. A comprehensive analysis of patients undergoing ICT is warranted to correlate expression of MHC-II neoantigens to response to ICT.

Alspach E, Lussier DM, Miceli AP, Kizhvatov I, DuPage M, Luoma AM, et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 2019;574:696–701.

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