Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer
Falguni Parikh, Dorothée Duluc, Naoko Imai, Amelia Clark, Krzys Misiukiewicz, Marcello Bonomi, Vishal Gupta, Alexis Patsias, Michael Parides, Elizabeth G Demicco, David Y Zhang, Seunghee Kim-Schulze, Johnny Kao, Sacha Gnjatic, Sangkon Oh, Marshall R Posner, Andrew G Sikora, Falguni Parikh, Dorothée Duluc, Naoko Imai, Amelia Clark, Krzys Misiukiewicz, Marcello Bonomi, Vishal Gupta, Alexis Patsias, Michael Parides, Elizabeth G Demicco, David Y Zhang, Seunghee Kim-Schulze, Johnny Kao, Sacha Gnjatic, Sangkon Oh, Marshall R Posner, Andrew G Sikora
Abstract
While viral antigens in human papillomavirus (HPV)-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from patients with stage III-IV oropharyngeal cancer undergoing concomitant chemoradiotherapy with or without induction chemotherapy. Circulating immunocytes including CD4(+) and CD8(+) T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T-cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T-cell assays in the presence of blocking antibody. While HPV-specific T-cell responses were present in 13 of 18 patients before treatment, 10 of 13 patients lost these responses within 3 months after chemoradiotherapy. Chemoradiotherapy decreased circulating T cells and markedly elevated MDSCs. PD-1 expression on CD4(+) T cells increased by nearly 2.5-fold after chemoradiotherapy, and ex vivo culture with PD-1-blocking antibody enhanced HPV-specific T-cell responses in 8 of 18 samples tested. Chemoradiotherapy suppresses circulating immune responses in patients with HPVOPC by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4(+) T cells. These data strongly support testing of PD-1-blocking agents in combination with standard-of-care chemoradiotherapy for HPVOPC.
Conflict of interest statement
CONFLICT OF INTEREST DISCLOSURE STATEMENT:
The corresponding author is the recipient of an unrestricted industry grant from Advaxis Pharmaceuticals for an investigator-initiated immunotherapy trial for HPV-positive oropharyngeal cancer.
©2014 American Association for Cancer Research.
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Source: PubMed