Exploring olfactory receptor family 7 subfamily C member 1 as a novel oral cancer stem cell target for immunotherapy

The mortality rate of oral cancer has not improved over the past three decades despite remarkable advances in cancer therapies. Oral cancers contain a subpopulation of cancer stem cells (CSCs) that share characteristics associated with normal stem cells, including self‐renewal and multi‐differentiation potential. CSCs are tumorigenic, play a critical role in cancer infiltration, recurrence, and distant metastasis, and significantly contribute to drug resistance to current therapeutic strategies, including immunotherapy. Cytotoxic CD8+ T lymphocytes (CTLs) are key immune cells that effectively recognize peptide antigens presented by the major histocompatibility complex class I molecules. Increasing evidence suggests that cancer antigen‐specific targeting by CTLs effectively regulates CSCs that drive cancer progression. In this study, we utilized data from public domains and performed various bioassays on human oral squamous cell carcinoma clinical samples and cell lines, including HSC‐2 and HSC‐3, to investigate the potential role of olfactory receptor family 7 subfamily C member 1 (OR7C1), a seven transmembrane G‐protein‐coupled olfactory receptor that is also expressed in nonolfactory tissues and was previously reported as a novel marker and target of colon cancer initiating cell‐targeted immunotherapy, in CSC‐targeted treatment against oral cancer. We found that the OR7C1 gene was expressed only in oral CSCs, and that CTLs reacted with human leukocyte antigen‐A24‐restricted OR7C1 oral CSC‐specific peptides. Taken together, our findings suggest that OR7C1 represents a novel target for potent CSC‐targeted immunotherapy in oral cancer. OR7C1 was found to be preferentially expressed in oral cancer stem cells (CSCs). OR7C1‐specific cytotoxic CD8+ T lymphocyte (CTL) clones could recognize HLA‐A24+ and OR7C1+ oral cancer cells and specifically lyse oral CSCs. The results indicate that OR7C1 is a reasonable candidate for treatment‐resistant CSC.