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Simple Summary: Intratumoral hypoxia is associated with poor prognosis and therapeutic resistance by modifying the tumor microenvironment in several cancers. MTH1, a member of the Nudix family, maintains the genomic integrity and viability of tumor cells under hypoxic conditions. This study aimed to investigate whether the antitumor activity of immune cells is effective under hypoxia and whether hypoxia-induced MTH1 could be a target for immunotherapy. We found that MTH1 expression is elevated in hypoxic head and neck cancer cell lines and tissues. A novel MTH1 epitope peptide activates CD4+ helper T cells with cytotoxic activity, and is effective even under hypoxic conditions. Combining MTH1-targeted immunotherapy with PD-1 blockade enhances cytotoxicity. These results suggest that MTH1-targeted immunotherapy combined with checkpoint blockade could effectively treat hypoxic tumors by maintaining T-cell activity and increasing cytotoxicity under hypoxic conditions. 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. [ABSTRACT FROM AUTHOR]

Background: The identification of epitope peptides from tumor‐associated antigens (TAAs) is informative for developing tumor‐specific immunotherapy. However, only a few epitopes have been detected in mouse TAAs of head and neck cancer (HNSCC). Methods: Novel mouse c‐Met‐derived T‐cell epitopes were predicted by computer‐based algorithms. Mouse HNSCC cell line‐bearing mice were treated with a c‐Met peptide vaccine. The effects of CD8 and/or CD4 T‐cell depletion, and vaccine combination with immune checkpoint inhibitors (ICIs) were evaluated. Tumor re‐inoculation was performed to assess T‐cell memory. Results: We identified c‐Met‐derived short and long epitopes that elicited c‐Met‐reactive antitumor CD8 and/or CD4 T‐cell responses. Vaccination using these peptides showed remarkable antitumor responses via T cells in which ICIs were not required. The c‐Met peptide‐vaccinated mice rejected the re‐inoculated tumors. Conclusions: We demonstrated that novel c‐Met peptide vaccines can induce antitumor T‐cell response, and could be a potent immunotherapy in a syngeneic mouse HNSCC model. [ABSTRACT FROM AUTHOR]

The recognition by cytotoxic T cells (CTLs) is essential for the clearance of SARS-CoV-2 virus-infected cells. Several viral proteins have been described to be recognized by CTLs. Among them, the spike (S) protein is one of the immunogenic proteins. The S protein acts as a ligand for its receptors, and several mutants with different affinities for its cognate receptors have been reported, and certain mutations in the S protein, such as L452R and Y453F, have been found to inhibit the HLA-A24-restricted CTL response. In this study, we conducted a screening of candidate peptides derived from the S protein, specifically targeting those carrying the HLA-A24 binding motif. Among these peptides, we discovered that NF9 (NYNYLYRLF) represents an immunogenic epitope. CTL clones specific to the NF9 peptide were successfully established. These CTL clones exhibited the ability to recognize endogenously expressed NF9 peptide. Interestingly, the CTL clone demonstrated cross-reactivity with the Y453F peptide (NYNYLFRLF) but not with the L452R peptide (NYNYRYRLF). The CTL clone was able to identify the endogenously expressed Y453F mutant peptide. These findings imply that the NF9-specific CTL clone possesses the capability to recognize and respond to the Y453F mutant peptide. [ABSTRACT FROM AUTHOR]

In CD70‐expressing tumors, the interaction of CD70 on tumor cells with its lymphocyte receptor, CD27, is thought to play a role in immunosuppression in the tumor microenvironment and elevated serum levels of soluble CD27 (sCD27). Previous studies showed that CD70 is expressed in nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV)‐related malignancy. However, the association between intratumoral CD70/CD27 expression and serum levels of sCD27 in NPC remains unclear. In the present study, we show that CD70 is primarily expressed by tumor cells in NPC and that CD27‐positive lymphocytes infiltrate around tumor cells. NPC patients with CD27‐positive lymphocytes had significantly better prognosis than patients lacking these cells. In addition, high CD70 expression by tumor cells tended to be correlated with shorter survival in NPC patients with CD27‐positive lymphocytes. Serum sCD27 levels were significantly increased in patients with NPC and provided good diagnostic accuracy for discriminating patients from healthy individuals. The concentration of serum sCD27 in patients with CD70‐positive NPC with CD27‐positive lymphocytes was significantly higher than in patients with tumors negative for CD70 and/or CD27, indicating that the intratumoral CD70/CD27 interaction boosts the release of sCD27. Furthermore, positive expression of CD70 by NPC cells was significantly correlated with EBV infection. Our results suggest that CD70/CD27‐targeted immunotherapies may be promising treatment options and that sCD27 may become an essential tool for evaluating the applicability of these therapies by predicting the intratumoral CD70/CD27 interaction in NPC. [ABSTRACT FROM AUTHOR]