Hypoxia-Targeted Immunotherapy with PD-1 Blockade in Head and Neck Cancer

Author:

Wakisaka Risa1,Yamaki Hidekiyo1,Kono Michihisa1ORCID,Inoue Takahiro1,Sato Ryosuke1ORCID,Komatsuda Hiroki1ORCID,Ohara Kenzo12ORCID,Kosaka Akemi3,Ohkuri Takayuki3,Nagato Toshihiro3ORCID,Kishibe Kan1,Nakayama Koh4,Kobayashi Hiroya3,Kumai Takumi12ORCID,Takahara Miki1

Affiliation:

1. Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa 0788510, Japan

2. Department of Innovative Head & Neck Cancer Research and Treatment (IHNCRT), Asahikawa Medical University, Asahikawa 0788510, Japan

3. Department of Pathology, Asahikawa Medical University, Asahikawa 0788510, Japan

4. Department of Pharmacology, Asahikawa Medical University, Asahikawa 0788510, Japan

Abstract

Intratumoral hypoxia is associated with tumor progression, aggressiveness, and therapeutic resistance in several cancers. Hypoxia causes cancer cells to experience replication stress, thereby activating DNA damage and repair pathways. MutT homologue-1 (MTH1, also known as NUDT1), a member of the Nudix family, maintains the genomic integrity and viability of tumor cells in the hypoxic tumor microenvironment. Although hypoxia is associated with poor prognosis and can cause therapeutic resistance by regulating the microenvironment, it has not been considered a treatable target in cancer. This study aimed to investigate whether hypoxia-induced MTH1 is a useful target for immunotherapy and whether hypoxic conditions influence the antitumor activity of immune cells. Our results showed that MTH1 expression was elevated under hypoxic conditions in head and neck cancer cell lines. Furthermore, we identified a novel MTH1-targeting epitope peptide that can activate peptide-specific CD4+ helper T cells with cytotoxic activity. The proliferation and cytotoxic activity of T cells were maintained under hypoxic conditions, and PD-1 blockade further augmented the cytotoxicity. These results indicate that MTH1-targeted immunotherapy combined with checkpoint blockade can be an effective strategy for the treatment of hypoxic tumors.

Funder

JSPS KAKENHI

Publisher

MDPI AG

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