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

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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
StatePublished - Dec 15 2014
Externally publishedYes

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Oropharyngeal Neoplasms
Chemoradiotherapy
Immunity
Up-Regulation
T-Lymphocytes
Blocking Antibodies
Standard of Care
Induction Chemotherapy
Viral Antigens
Regulatory T-Lymphocytes
Immunotherapy
Immunosuppression
Flow Cytometry
Therapeutics
Antigens
Peptides

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

Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer. / Parikh, Falguni; Duluc, Dorothée; Imai, Naoko; Clark, Amelia; Misiukiewicz, Krzys; Bonomi, Marcello; Gupta, Vishal; Patsias, Alexis; Parides, Michael; Demicco, Elizabeth G.; Zhang, David Y.; Kim-Schulze, Seunghee; Kao, Johnny; Gnjatic, Sacha; Oh, SangKon; Posner, Marshall R.; Sikora, Andrew G.

In: Cancer Research, Vol. 74, No. 24, 15.12.2014, p. 7205-7216.

Research output: Contribution to journalArticle

Parikh, F, Duluc, D, Imai, N, Clark, A, Misiukiewicz, K, Bonomi, M, Gupta, V, Patsias, A, Parides, M, Demicco, EG, Zhang, DY, Kim-Schulze, S, Kao, J, Gnjatic, S, Oh, S, Posner, MR & Sikora, AG 2014, 'Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer', Cancer Research, vol. 74, no. 24, pp. 7205-7216. https://doi.org/10.1158/0008-5472.CAN-14-1913
Parikh, Falguni ; Duluc, Dorothée ; Imai, Naoko ; Clark, Amelia ; Misiukiewicz, Krzys ; Bonomi, Marcello ; Gupta, Vishal ; Patsias, Alexis ; Parides, Michael ; Demicco, Elizabeth G. ; Zhang, David Y. ; Kim-Schulze, Seunghee ; Kao, Johnny ; Gnjatic, Sacha ; Oh, SangKon ; Posner, Marshall R. ; Sikora, Andrew G. / Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer. In: Cancer Research. 2014 ; Vol. 74, No. 24. pp. 7205-7216.
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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.",
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AU - Bonomi, Marcello

AU - Gupta, Vishal

AU - Patsias, Alexis

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AU - Demicco, Elizabeth G.

AU - Zhang, David Y.

AU - Kim-Schulze, Seunghee

AU - Kao, Johnny

AU - Gnjatic, Sacha

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AU - Sikora, Andrew G.

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