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.
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