title: Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer.
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.
authors.affiliation: Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Falguni
authors.initials: F
authors.lastname: Parikh
authors.affiliation: Baylor Institute of Immunology, Dallas, Texas.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Duluc
authors.affiliation: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Naoko
authors.initials: N
authors.lastname: Imai
authors.affiliation: Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Amelia
authors.initials: A
authors.lastname: Clark
authors.affiliation: Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Krzys
authors.initials: K
authors.lastname: Misiukiewicz
authors.affiliation: Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Marcello
authors.initials: M
authors.lastname: Bonomi
authors.affiliation: Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Vishal
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Alexis
authors.initials: A
authors.lastname: Patsias
authors.affiliation: Health Evidence and Policy, Program, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Parides
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Demicco
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: David Y
authors.initials: DY
authors.lastname: Zhang
authors.affiliation: Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Kim-Schulze
authors.affiliation: Department of Radiation Oncology, Good Samaritan Hospital Medical Center, West Islip, New York.
authors.forename: Johnny
authors.initials: J
authors.lastname: Kao
authors.affiliation: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.affiliation: Baylor Institute of Immunology, Dallas, Texas.
authors.forename: Sangkon
authors.initials: S
authors.lastname: Oh
authors.affiliation: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Marshall R
authors.initials: MR
authors.lastname: Posner
authors.affiliation: Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. andrew.sikora@BCM.edu.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sikora
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D059248:Chemoradiotherapy; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D060828:Induction Chemotherapy; D009367:Neoplasm Staging; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis / Q000378:metabolism; D030361:Papillomavirus Infections / Q000235:genetics / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis* / Q000276:immunology
chemical_list: C105992:PDCD1 protein, human; D050725:Papillomavirus E7 Proteins; D061026:Programmed Cell Death 1 Receptor