Adoptive T-cell Transfer Targets Viral and Nonviral Tumor Antigens

Immunotherapy has antitumor activity in a subset of virally induced cancers, including human papillomavirus (HPV)–induced cervical cancer. However, the specific tumor antigens targeted by successful immunotherapy have not been determined. Stevanović and colleagues performed a global landscape analysis of the viral and nonviral tumor antigens targeted by T cells in two patients with HPV⁺ metastatic cervical carcinoma who experienced complete tumor regression after adoptive transfer of tumor-infiltrating lymphocytes (TIL). Both patients' TILs harbored T cells specific for the viral HPV antigens. Infused TILs also had activity against private neoantigens generated by somatic mutations in one patient, and a cancer germline antigen KK-LC-1 in the other patient, indicating that T cells target nonviral tumor antigens in addition to HPV oncoproteins in successful immunotherapy. Further, both patients received TILs with a low frequency of HPV-targeted T cells. In TILs from one patient, HPV-specific T-cell receptor (TCR) clonotypes accounted for 14% and mutated neoantigen-specific TCR clonotypes accounted for 35% of all T cells. In the other patient, the KK-LC-1–specific TCR clonotype accounted for 67% and the HPV-E7–specific TCR clonotype accounted for 14% of all T cells. In both patients the infused tumor antigen–reactive T cells persisted at elevated levels and remained functional during tumor regression and remission. The viral antigen–targeting T cells did not display preferential expansion in vivo. PD-1 was expressed on less than 10% of the CD4⁺ and CD8⁺ T cells before treatment in both patients, but different viral and nonviral tumor antigen–specific T-cell clonotypes were found only on PD-1⁺ T cells, indicating that PD-1 expression may identify T cells specific for both viral and nonviral tumor antigens. These results reveal a role for T cells in targeting nonviral tumor antigens in adoptive T-cell therapy in patients with HPV⁺ cervical cancer, suggesting that neoantigens and cancer germline antigens may represent therapeutic targets in HPV-driven cancer.

Stevanović S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 2017;356:200–5.

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