Landscape of immunogenic tumor antigens in successful immunotherapy of virally-induced epithelial cancer
S. Stevanović1*, A. Pasetto2, S.R. Helman1, J.J. Gartner2, T.D. Prickett2, B. Howie3, H.S. Robins3,4, P.F. Robbins2, C.A. Klebanoff5, S.A. Rosenberg2, C.S. Hinrichs1
1Experimental Transplantation and Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892. 2Surgery Branch, NCI, NIH, Bethesda, MD 20892. 3Adaptive Biotechnologies, Seattle, WA 98102.4Fred Hutchinson Cancer Research Center, Seattle, WA 98109. 5Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065
Immunotherapy has clinical activity in human papillomavirus (HPV)-induced epithelial cancers, but the tumor antigens targeted by T cells resulting in cancer regression remain poorly defined. The viral antigens expressed by HPV+ tumors are considered the primary targets of T-cell based immune attack. However, HPV+ cancers also harbor somatic mutations and express cancer-germline antigens that may be targets of tumor-specific T cells. We used an immunogenomic approach to elucidate the global landscape of the viral and non-viral tumor antigens targeted by T cells in patients who experienced complete regression of HPV+ metastatic cervical cancer after tumor-infiltrating adoptive T-cell therapy. Remarkably, T cells directed against HPV-derived antigens represented a subdominant population of infused tumor-specific T cells. Instead, the predominant tumor-specific T-cell population targeted mutated neoantigens in one patient and the cancer-germline antigen Kita-kyushu lung cancer antigen 1 in another patient. Furthermore, T cells targeting viral tumor antigens did not display preferential in vivo expansion during cancer regression. Finally, T-cell clonotypes specific for both viral and non-viral tumor antigens resided predominantly in the programmed cell death 1 (PD-1)+ T-cell compartment, suggesting that PD-1 blockade in HPV+ cancers may unleash diverse anti-tumor T-cell reactivity. These findings suggest a new paradigm of targeting non-viral antigens in immunotherapy of HPV+ cancers.