Epigenetically controlled tumor antigens derived from splice junctions between exons and transposable elements

Abstract

Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons and TEs represent a source of tumor-specific antigens. We show that mouse normal tissues and tumor cell lines express wide but distinct ranges of mRNA junctions between exons and TEs, some of which are tumor specific. Immunopeptidome analyses in tumor cell lines identified peptides derived from exon-TE splicing junctions associated to MHC-I molecules. Exon-TE junction–derived peptides were immunogenic in tumor-bearing mice. Both prophylactic and therapeutic vaccinations with junction-derived peptides delayed tumor growth in vivo. Inactivation of the TE-silencing histone 3–lysine 9 methyltransferase Setdb1 caused overexpression of new immunogenic junctions in tumor cells. Our results identify exon-TE splicing junctions as epigenetically controlled, immunogenic, and protective tumor antigens in mice, opening possibilities for tumor targeting and vaccination in patients with cancer.

Noncanonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in patients with lung cancer

“…SETDB-1 –low samples differentially expressed more JETs than SETDB-1 –high samples (fig. S1D), consistent with our results in mouse tumors ( 28 ). These results suggest that TE derepression in tumors can influence JET expression.…”

“…We detected JET-specific T cell responses in tumors and lymph nodes from patients with NSCLC at steady state and after in vitro culture. These findings are consistent with our companion paper showing that murine JETs are immunogenic and protective in vivo ( 28 ). A second technique for the detection of JET-specific T cells in tumors/lymph nodes (such as enzyme-linked immunospot), however, would strengthen the evidence for anti-JET T cell responses in patients.…”

“…We also show that, in addition to being tumor specific or tumor associated, JETs can be shared between patients, most likely due to recurrent alterations in the splicing machinery and TE derepression landscape in cancer cells. Our results in mice ( 28 ) show that derepression of TEs through ablation of the epigenetic silencer Setdb-1 modifies JET expression. In line with these results, we observe that numerous JETs are differentially expressed in human NSCLC patients with low levels of SETDB-1 .…”

Allogeneic Tumor Cell-Derived Extracellular Vesicles Stimulate CD8 T Cell Response in Colorectal Cancer

“…It has been reported that there are conserved tumor exon junctions between MC38 colon cancer cells B16-F10 melanoma cells that can be presented on MHCI. 29 Additionally, mice exposed prophylactically to conserved tumor exon junctions showed protective effects against B16-F10 growth through induction of anti-tumor immune responses. 29 We speculate that conserved tumor neoantigens between MC38 TEVs and B16-F10 melanoma may undergo immunoediting, thus allowing for immune escape.…”

“…29 Additionally, mice exposed prophylactically to conserved tumor exon junctions showed protective effects against B16-F10 growth through induction of anti-tumor immune responses. 29 We speculate that conserved tumor neoantigens between MC38 TEVs and B16-F10 melanoma may undergo immunoediting, thus allowing for immune escape. 30,31 Conversely, the tumor neoantigens conserved between MC38 TEVs and B16-F10 may only stimulate a weak immune response.…”