Wakisaka Risa, Yamaki Hidekiyo, Kono Michihisa, Inoue Takahiro, Sato Ryosuke, Komatsuda Hiroki, Ohara Kenzo, Kosaka Akemi, Ohkuri Takayuki, Nagato Toshihiro, Kishibe Kan, Nakayama Koh, Kobayashi Hiroya, Kumai Takumi, Takahara Miki
Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa 0788510, Japan.
Department of Innovative Head & Neck Cancer Research and Treatment (IHNCRT), Asahikawa Medical University, Asahikawa 0788510, Japan.
Cancers (Basel). 2024 Aug 29;16(17):3013. doi: 10.3390/cancers16173013.
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.
肿瘤内缺氧与多种癌症的肿瘤进展、侵袭性和治疗抗性相关。缺氧使癌细胞经历复制应激，从而激活DNA损伤和修复途径。MutT同源物1（MTH1，也称为NUDT1）是Nudix家族的成员，在缺氧的肿瘤微环境中维持肿瘤细胞的基因组完整性和活力。尽管缺氧与预后不良相关，并且可通过调节微环境导致治疗抗性，但它尚未被视为癌症的可治疗靶点。本研究旨在调查缺氧诱导的MTH1是否是免疫治疗的有用靶点，以及缺氧条件是否影响免疫细胞的抗肿瘤活性。我们的结果表明，在头颈部癌细胞系的缺氧条件下，MTH1表达升高。此外，我们鉴定出一种新型的靶向MTH1的表位肽，其可激活具有细胞毒性活性的肽特异性CD4+辅助性T细胞。T细胞的增殖和细胞毒性活性在缺氧条件下得以维持，并且PD-1阻断进一步增强了细胞毒性。这些结果表明，靶向MTH1的免疫治疗联合检查点阻断可能是治疗缺氧肿瘤的有效策略。
