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、侵袭性及治疗抵抗相关。缺氧导致癌细胞经历复制应激，从而激活DNA损伤与修复通路。MutT同源物1（MTH1，亦称NUDT1）作为Nudix家族成员，在缺氧肿瘤微环境中维持肿瘤细胞的基因组完整性和生存能力。尽管缺氧与不良预后相关，并能通过调控微环境导致治疗抵抗，但其尚未被视为癌症的可治疗靶点。本研究旨在探讨缺氧诱导的MTH1是否可作为免疫治疗的有效靶点，以及缺氧条件是否影响免疫细胞的抗肿瘤活性。研究结果显示，在头颈癌细胞系中，MTH1表达在缺氧条件下显著升高。此外，我们鉴定出一种新型MTH1靶向表位肽，能够激活具有细胞毒活性的肽特异性CD4+辅助T细胞。T细胞的增殖与细胞毒活性在缺氧条件下得以维持，且PD-1阻断进一步增强了其细胞毒性。这些结果表明，靶向MTH1的免疫治疗联合检查点阻断，可能成为治疗缺氧肿瘤的有效策略。
Hypoxia-Targeted Immunotherapy with PD-1 Blockade in Head and Neck Cancer
肿瘤(癌症)患者之家