Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens
Kwok, D. W.; Stevers, N. O.; Nejo, T.; Chen, L. H.; Etxeberria, I.; Jung, J.; Okada, K.; Colton Cove, M.; Lakshmanachetty, S.; Gallus, M.; Barpanda, A.; Hong, C.; Chan, G. K. L.; Wu, S. H.; Ramos, E.; Yamamichi, A.; Liu, J. Y. Z.; Watchmaker, P.; Ogino, H.; Saijo, A.; Du, A.; Grishanina, N.; Woo, J.; Diaz, A.; Chang, S. M.; Phillips, J. J.; Wiita, A.; Klebanoff, C. A.; Costello, J. F.; Okada, H.
Show abstract
T-cell-mediated immunotherapies are limited by the extent to which cancer-specific antigens are homogenously expressed throughout a tumor. We reasoned that recurrent splicing aberrations in cancer represent a potential source of tumor-wide and public neoantigens, and to test this possibility, we developed a novel pipeline for identifying neojunctions expressed uniformly within a tumor across diverse cancer types. Our analyses revealed multiple neojunctions that recur across patients and either exhibited intratumor heterogeneity or, in some cases, were tumor-wide. We identified CD8+ T-cell clones specific for neoantigens derived from tumor-wide and conserved neojunctions in GNAS and RPL22, respectively. TCR-engineered CD8+ T-cells targeting these mutations conferred neoantigen-specific tumor cell eradication. Furthermore, we revealed that cancer-specific dysregulation in splicing factor expression leads to recurrent neojunction expression. Together, these data reveal that a subset of neojunctions are both intratumorally conserved and public, providing the molecular basis for novel T-cell-based immunotherapies that address intratumoral heterogeneity.
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