Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer

Immunotherapy has clinical activity in certain virally associated cancers. However, the tumor antigens targeted in successful treatments remain poorly defined.We used a personalized immunogenomic approach to elucidate the global landscape of antitumor T cell responses in complete regression of human papillomavirus-associated metastatic cervical cancer after tumor-infiltrating adoptive Tcell therapy. Remarkably, immunodominant Tcell reactivities were directed againstmutated neoantigens or a cancer germline antigen, rather than canonical viral antigens.Tcells targeting viral tumor antigens did not display preferential in vivo expansion. Both viral and nonviral tumor antigen-specificTcells resided predominantly in the programmed cell death 1 (PD-1)-expressing Tcell compartment, which suggests that PD-1 blockade may unleash diverse antitumor Tcell reactivities.These findings suggest a new paradigm of targeting nonviral antigens in immunotherapy of virally associated cancers.