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

Research output: Contribution to journalArticle

46 Scopus citations

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-speci fi c 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 de fi ned 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.

Original languageEnglish (US)
Pages (from-to)7205-7216
Number of pages12
JournalCancer Research
Volume74
Issue number24
DOIs
Publication statusPublished - Dec 15 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Parikh, F., Duluc, D., Imai, N., Clark, A., Misiukiewicz, K., Bonomi, M., ... Sikora, A. G. (2014). Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer. Cancer Research, 74(24), 7205-7216. https://doi.org/10.1158/0008-5472.CAN-14-1913