Matsushima et al. reported that splice variant-inducing synthetic compound RECTAS promotes antitumor immunogenicity through induction of splice-neoantigens. In the MC38 tumor model, RECTAS-induced activation of Ser/Arg-rich splicing factors (SRSFc), suppressed tumor growth, prolonged survival, and improved the efficacy of PD-1 blockade in a CD8+ T cell- and MHC class I-dependent manner. RNAseq analysis and ex vivo validation identified six RECTAS-induced splice-neoantigen candidates. Vaccination with the neoepitopes elicited T cell response in vitro and promoted RECTAS-induced antitumor immune responses in vivo.
Contributed by Shishir Pant
ABSTRACT: Neoantigen production is a determinant of cancer immunotherapy. However, the expansion of neoantigen abundance for cancer therapeutics is technically challenging. Here, we report that the synthetic compound RECTAS can induce the production of splice-neoantigens that could be used to boost antitumor immune responses. RECTAS suppressed tumor growth in a CD8(+) T cell- and tumor major histocompatibility complex class I-dependent manner and enhanced immune checkpoint blockade efficacy. Subsequent transcriptome analysis and validation for immunogenicity identified six splice-neoantigen candidates whose expression was induced by RECTAS treatment. Vaccination of the identified neoepitopes elicited T cell responses capable of killing cancer cells in vitro, in addition to suppression of tumor growth in vivo upon sensitization with RECTAS. Collectively, these results provide support for the further development of splice variant-inducing treatments for cancer immunotherapy.