Chemoradiotherapy-Induced Upregulation of PD-1 Antagonizes Immunity to HPV-Related Oropharyngeal Cancer

Parikh, Falguni; Duluc, Dorothée; Imai, Naoko; Clark, Amelia; Misiukiewicz, K.; Bonomi, Marcello; Gupta, Vishal; Patsias, Alexis; Parides, Michael K.; Demicco, Elizabeth G.; Zhang, David Y.; Kim‐Schulze, Seunghee; Kao, Johnny; Gnjatic, Sacha; Oh, SangKon; Posner, Marshall R.; Sikora, Andrew G.

doi:10.1158/0008-5472.can-14-1913

Cited by 85 publications

(73 citation statements)

References 43 publications

(44 reference statements)

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“…Chemoradiotherapy was also reported to be immune suppressive in patients with HPV-related oropharyngeal cancer 25 . A decrease in CD4 + and CD8 + T cells, an increase of MDSCs and an unfavorable CD8 + /Treg ratio upon radiation treatment was seen.…”

Section: Discussionmentioning

confidence: 95%

Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients

et al. 2017

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New treatments based on combinations of standard therapeutic modalities and immunotherapy are of potential use, but require a profound understanding of immune modulatory properties of standard therapies. Here, the impact of standard (chemo)radiotherapy on the immune system of cervical cancer patients was evaluated. Thirty patients with cervical cancer were treated with external beam radiation therapy (EBRT), using conventional three-dimensional or intensity modulated radiation therapy without constraints for bone marrow sparing. Serial blood sampling for immunomonitoring was performed before, midway and at 3, 6 and 9 weeks after EBRT to analyze the composition of lymphocyte and myeloid-cell populations, the expression of co-stimulatory molecules, T-cell reactivity and antigen presenting cell (APC) function. Therapy significantly decreased the absolute numbers of circulating leukocytes and lymphocytes. Furthermore, the capacity of the remaining T cells to respond to antigenic or mitogenic stimulation was impaired. During treatment the frequency of both CD4+ and CD8+ T cells dropped and CD4+ T cells displayed an increased expression of programmed cell death-1 (PD-1). In vitro blocking of PD-1 successfully increased T-cell reactivity in all five samples isolated before radiotherapy but was less successful in restoring reactivity in samples isolated at later time points. Moreover, (chemo)radiotherapy was associated with an increase in both circulating monocytes and myeloid-derived suppressor cells (MDSCs) and an impaired capacity of APCs to stimulate allogeneic T cells. T-cell reactivity was slowly restored at 6–9 weeks after cessation of therapy. We conclude that conventional (chemo)radiotherapy profoundly suppresses the immune system in cervical cancer patients, and may restrict its combination with immunotherapy.

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Section: Discussionmentioning

confidence: 95%

Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients

et al. 2017

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“…Among other mechanisms, the programmed death-1 and programmed death ligand 1 (PD-1/PD-L1) pathway appears to be a key contributor to immune resistance of HPV-related OPC (28 (32). In patients with HPV þ OPC, HPV-specific T-cell responses were reduced, PD-1 expression was increased on CD4 þ T cells, and myeloid-derived suppressor cells increased, following chemoradiation (33). All of these data provide rationale for investigation of checkpoint inhibition in HPV þ OPC in all settings of treatment, with the hope not only of improving efficacy of treatment in high-risk patients but also of reducing late effects through integration in deintensification approaches.…”

Section: Reversing Immune Evasionmentioning

confidence: 99%

“…Addition of immunotherapy to definitive concurrent chemoradiotherapy is also a promising strategy given the recently reported data regarding immunosuppression, broad and HPVspecific, following treatment (33 This agent will also be studied with reirradiation (Table 2). A phase III trial of anti-PD-1 nivolumab versus investigator's choice therapy is ongoing in platinum-refractory metastatic/ recurrent HPV-related and unrelated HNSCC and a similarly designed trial is planned with pembrolizumab ( Table 2).…”

Section: Reversing Immune Evasionmentioning

confidence: 99%

New Strategies in Human Papillomavirus–Related Oropharynx Cancer: Effecting Advances in Treatment for a Growing Epidemic

Massarelli

Ferrarotto

Glisson

2015

Clinical Cancer Research

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The past two decades have been witness to a steadily increasing incidence of oropharynx cancer, specifically related to human papillomavirus (HPV), primarily affecting middle-aged Caucasian men, in North America and Europe. The ever-increasing incidence, now clearly an epidemic, of this unique clinicopathologic entity demands new perspectives in diagnosis and staging and presents unique challenges in clinical research, given the excellent prognosis afforded by chemoradiation for the majority of these patients. To reduce the morbidity of late toxicity in survivors without compromising the high rates of survival currently enjoyed, and simultaneously address the poor prognosis of those with recurrence, it is critical to capitalize on the viral etiology and translate discoveries in genomics, target/drug discovery, viral oncogenesis, and immunbiology to improved outcomes for patients. Herein, we review ongoing and planned clinical research for HPV-related oropharynx cancer, the basis for which is constituted by prior clinical observations, knowledge of the genomic alterations and altered biology associated with HPV-related oncogenesis, and hope that molecularly targeted and immunomodulatory therapies can be harnessed. Clin Cancer Res; 21(17); 3821-8. Ó2015 AACR. Disclosure of Potential Conflicts of Interest Editor's DisclosuresThe following editor(s) reported relevant financial relationships: J.L. Abbruzzese is a consultant/advisory board member for Celgene and Halozyme. Learning ObjectivesUpon completion of this activity, the participant should have increased knowledge regarding the epidemiology and clinical presentation of HPV-related oropharynx cancer, understand the rationale for deintensification and be familiar with clinical research strategies to reduce late effects in curative-intent treatment, and be aware of the biologic rationale for strategies targeting the immune system and molecular alterations in treatment of relapsed and refractory cancer.

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“…It is mostly mediated by IFN-gamma-producing T cells (22). Furthermore, chemoradiation led to increased PD-1 expression on CD4+ T cells in the peripheral blood of patients with human papillomavirus-related oropharyngeal cancer (23). …”

Section: Introductionmentioning

confidence: 99%

Chemoradiation Increases PD-L1 Expression in Certain Melanoma and Glioblastoma Cells

et al. 2016

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Immunotherapy approaches currently make their way into the clinics to improve the outcome of standard radiochemotherapy (RCT). The programed cell death receptor ligand 1 (PD-L1) is one possible target that, upon blockade, allows T cell-dependent antitumor immune responses to be executed. To date, it is unclear which RCT protocol and which fractionation scheme leads to increased PD-L1 expression and thereby renders blockade of this immune suppressive pathway reasonable. We therefore investigated the impact of radiotherapy (RT), chemotherapy (CT), and RCT on PD-L1 surface expression on tumor cells of tumor entities with differing somatic mutation prevalence. Murine melanoma (B16-F10), glioblastoma (GL261-luc2), and colorectal (CT26) tumor cells were treated with dacarbazine, temozolomide, and a combination of irinotecan, oxaliplatin, and fluorouracil, respectively. Additionally, they were irradiated with a single dose [10 Gray (Gy)] or hypo-fractionated (2 × 5 Gy), respectively, norm-fractionated (5 × 2 Gy) radiation protocols were used. PD-L1 surface and intracellular interferon (IFN)-gamma expression was measured by flow cytometry, and IL-6 release was determined by ELISA. Furthermore, tumor cell death was monitored by AnnexinV-FITC/7-AAD staining. For first in vivo analyses, the B16-F10 mouse melanoma model was chosen. In B16-F10 and GL261-luc2 cells, particularly norm-fractionated and hypo-fractionated radiation led to a significant increase of surface PD-L1, which could not be observed in CT26 cells. Furthermore, PD-L1 expression is more pronounced on vital tumor cells and goes along with increased levels of IFN-gamma in the tumor cells. In melanoma cells CT was the main trigger for IL-6 release, while in glioblastoma cells it was norm-fractionated RT. In vivo, fractionated RT only in combination with dacarbazine induced PD-L1 expression on melanoma cells. Our results suggest a tumor cell-mediated upregulation of PD-L1 expression following in particular chemoradiation that is not only dependent on the somatic mutation prevalence of the tumor entity.

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Chemoradiotherapy-Induced Upregulation of PD-1 Antagonizes Immunity to HPV-Related Oropharyngeal Cancer

Cited by 85 publications

References 43 publications

Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients

Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients

New Strategies in Human Papillomavirus–Related Oropharynx Cancer: Effecting Advances in Treatment for a Growing Epidemic

Chemoradiation Increases PD-L1 Expression in Certain Melanoma and Glioblastoma Cells

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