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

S. Stevanović^1*, A. Pasetto², S.R. Helman¹, J.J. Gartner², T.D. Prickett², B. Howie³, H.S. Robins^3,4, 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.