Human papillomavirus (HPV) type 16 infection is one of the most important etiological agents of oropharyngeal squamous cell carcinoma. Patients with HPV-positive squamous cell carcinomas of the head and neck… Click to show full abstract
Human papillomavirus (HPV) type 16 infection is one of the most important etiological agents of oropharyngeal squamous cell carcinoma. Patients with HPV-positive squamous cell carcinomas of the head and neck were reported to have a better clinical outcome than patients with HPV-negative tumors. Because HPV16 E6 and E7 oncoproteins are highly immunogenic and constitutively expressed within the tumor cells, HPV-specific T cell immunity may contribute to the better prognosis of HPV-positive tumors. We analyzed the frequency, phenotype and function of HPV16 E6/E7-specific tumor-infiltrating T cells (TILs) in oropharyngeal tumors and tested the effect of anti-PD1 mAb (nivolumab), soluble Tim-3 (sTim-3) and homeostatic in vitro expansion on these characteristics. We show that 73.1% of HPV-associated oropharyngeal tumors are positive for HPV16-specific T cells capable of producing IFNγ upon stimulation with E6/E7 peptide pools. These IFNγ-producing HPV-specific TILs were mainly PD-1+Tim-3-CD8+ T cells, identifying Tim-3 rather than PD-1 as a marker of T cell dysfunction. Consequently, specific IFNγ production was further enhanced by combined nivolumab plus sTim-3 treatment, but not with nivolumab alone. Our data provide the rationale for exploring additional setups of anti-PD-1 mAb treatment, including combinations with other check-point blockers, such as Tim-3 and/or with HPV16-directed therapeutic vaccines. Citation Format: Simona Partlova, Kamila Hladikova, Vladimir Koucky, Anna Fialova, Radek Spisek, Jan Boucek, Michal Zabrodsky, Michael Halaska, Ruth Tachezy, Marek Grega, Jean-Francois Fonteneau. Dysfunction of HPV16-specific CD8+ T cells derived from oropharyngeal tumors is related to the expression of Tim-3 but not PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1002.
               
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