Purpose/Objectives: While viral antigens in HPV-related oropharyngeal cancer (HPVOPC) make it an attractive target for immunotherapy, understanding the immune effects of existing therapeutic approaches is essential for integrating immunotherapy into HPVOPC treatment. Preclinical data in several cancer models support an overall immunostimulatory effect of chemotherapy and radiation; however their effect on HPV-specific immunity on HPVOPC patients is unknown. We tested the hypotheses that platinum-based concomitant chemoradiation, with or without taxane-platinum-5FU (TPF) induction chemotherapy, induces a favorable profile of circulating immunocytes ad enhanced HPV-specific T cell responses in HPVOPC patients.
Materials/Methods: Patients with stage II-IV HPVOPC treated with standard-of-care chemoradiation underwent serial blood sampling before, during, and after treatment for up to one year. Circulating immunocytes including effector CD4+ and CD8+ T cells and immunosuppressive regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Expression levels of the negative costimulatory molecule PD-1 on T cells were also assessed by flow cytometry. HPV antigen-specific T cell responses in response to HPV16 E6 and E7 peptides were measured by luminex analysis of IFN-γ production.
Results: Pre-treatment HPV-specific T cell responses were present in 12/18 patients, and an additional 4 patients acquired measureable responses following induction chemotherapy. Of the 16 patients who developed HPV-specific responses before completion of therapy, 10 lost these responses by 3 months post-treatment. The average level of IFN-g release by PBMC after stimulation with HPV peptides was non-significantly decreased at 3 weeks post-treatment, and significantly decreased at 3 and 6 months. Loss of pre-existing tumor-specific immune responses was associated with a striking (2-fold) decline in circulating CD4+ and CD8+ T cell numbers, a lesser decline in Treg (1.5-fold), marked elevation of MDSC (>2-fold), and decline in the CD8+:Treg and CD8+:MDSC ratios following chemoradiotherapy. PD-1 expression levels on total and CD45RO+ (memory) CD4+ T cells were elevated at 3 weeks after completion of chemoradiation, returning to baseline by 3 months.
Conclusions: Contrary to our starting hypothesis, we found an overall immunosuppressive effect of chemoradiotherapy on immune responses in HPVOPC patients. Upregulation of PD-1 on CD4 T cells is a potential immunosuppressive mechanism amenable to targeted therapy with clinically available anti-PD-1 and anti-PD-L1 antibodies. Taken together, our results suggest that chemoradiation has profound effects on circulating immunocyte populations and the immune response to HPV+ OPC, and highlight the importance of further studies of the immune effects of standard-of-care treatment for HPVOPC.
Citation Format: Andrew Sikora, Marshall Posner, Falguni Parikh, Seunghee Kim-Schulze, Vishal Gupta, Krzysztof Misiukiewicz, Alexis Patsias, Amelia Clark, Sangkon Oh, Dorothee Duluc. Cisplatin-based concurrent chemoradiotherapy antagonizes anti-tumor immunity in patients with HPV-positive oropharyngeal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 626. doi:10.1158/1538-7445.AM2014-626