Abstract
Pharmacologic inhibition of RNA splicing produces immunogenic neoepitopes driving T-cell expansion.
Major Finding: Pharmacologic inhibition of RNA splicing produces immunogenic neoepitopes driving T-cell expansion.
Concept: Suppression of RNA splicing inhibited growth of tumor cells in mice and increased response to PD-1 inhibitors.
Impact: RNA splicing inhibition may be a potential way to induce tumor neoantigen production and increase antitumor immunity.
Genomic DNA mutations can give rise to neoantigens that influence the response to immune checkpoint blockade therapies, with a higher tumor mutational burden typically predicting better response. However, many cancers typically lack significant numbers of neoantigens, and immune checkpoint inhibition is not effective. RNA splicing in cells has also been proposed to be a source of neoantigens, but this has not currently been extensively studied. Using cancer cell lines engrafted into mice, Lu, De Neef, Thomas, and colleagues found that pharmacologic modulation of RNA splicing suppressed tumor growth in a dose-dependent manner, affecting host T cells and the presentation of MHC I tumor peptides by host antigen-presenting cells. The immunomodulatory effect of several different splicing modulators was evaluated on stimulated splenic T cells in mice, showing that SF3B inhibitors ablated T-cell activation and proliferation, but agents that degraded RBM39 or PRMTs did not cause any significant T-cell toxicity. Mice engrafted with syngeneic tumors and treated with combinations of splicing inhibitors and anti–PD-1 displayed a greater inhibition of tumor growth and longer survival than mice treated with splicing inhibitors or anti–PD-1 alone, and some anti–PD-1 resistant cell lines were resensitized with the addition of splicing inhibitors. RNA sequencing and MHC I immunopeptide data from murine tumor cell lines treated with splicing inhibitors revealed several hundred unique neoantigen candidates across diverse tumor types. Further analysis of these unique neoepitopes revealed targeted immunogenicity, and several neoepitopes were associated with expansion of CD8+ T cells in vivo. In summary, the authors demonstrate that RNA splicing modulation can acutely induce the production of neoantigens, and pharmacologic inhibition of splicing sensitizes tumor cells to immune checkpoint inhibition.
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