CMTM6 status predicts survival in head and neck squamous cell carcinoma and correlates with PD-L1 expression

We retrospectively analyzed 129 treatment-naïve head and neck squamous cell carcinomas (HNSCCs) for the expression of programmed death ligand 1 (PD-L1), CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6), tumor-infiltrating leukocytes (TILs), and tumor-associated macrophages (TAMs). We evaluated the relationships among these markers, human papilloma virus (HPV) status, and overall survival (OS). PD-L1 and CMTM6 (combined positive score (CPS) ≥ 1 and ≥ 5) were detected in ~ 70% of HNSCCs. HPV status had insignificant effects on marker expression. Most PD-L1-positive cases showed concomitant CMTM6 expression with comparable staining patterns. While PD-L1 and CMTM6 mRNA expression levels correlated with PD-L1 and CMTM6 protein status, no significant correlation was observed for PD-L1 and CMTM6 mRNA expression. Tumors expressing PD-L1 (p < 0.0001) and/or CMTM6 (p < 0.05) were associated with the best OS. A high density of TILs (p < 0.01), CD8⁺ T cells (p < 0.001), and CD68/CD163 ratio > 1 were prognostically relevant. In addition to HPV status, PD-L1 and CD8⁺ T cells, CMTM6 was identified as an independent prognostic factor using a multivariate Cox regression analysis. PD-L1 and CMTM6 correlated with TILs and CD8⁺ cells but not with HPV. Our results identified CMTM6 as an important interaction partner in the crosstalk between TILs, CD8⁺ T cells, and PD-L1, which mediates anticancer efficacy. Assessments of CMTM6 may be helpful for prognostic prediction, and it may serve as a reliable biomarker for immunotherapy selection.