Background: Renal cell carcinoma (RCC) is characterized by considerable heterogeneity and variable clinical outcomes. The identification of reliable biomarkers is crucial to improve prognostic assessment and therapeutic decision-making. CMTM6 (chemokine-like factor-like MARVEL transmembrane domain-containing protein 6) has emerged as a regulator of programmed death ligand-1 (PD-L1), a key immune checkpoint protein involved in tumor immune evasion. Objectives: The main objective of the study was to investigate the expression and prognostic significance of CMTM6 and to establish an automated immunohistochemical analysis. Design: This was a retrospective analysis conducted at a single center. Methods: Tumor samples from 111 patients who underwent partial nephrectomy for localized RCC between 2006 and 2019 were retrospectively analyzed. CMTM6 expression in tumor cells and tumor-infiltrating immune cells (ICs) was quantified using automated digital image analysis of immunohistochemically stained slides. Associations between CMTM6 expression, clinicopathological features, and patient outcomes were evaluated. Results: CMTM6 expression was heterogeneous across RCC samples, with significantly higher levels observed in clear cell RCC compared to non-clear cell subtypes. Elevated CMTM6 expression in ICs correlated with reduced overall survival ( p = 0.049) and shorter time to metastasis ( p = 0.009). Conversely, in patients with metastatic RCC receiving systemic therapy, lower CMTM6 expression was associated with shorter progression-free survival ( p = 0.047). However, lower CMTM6 scores were also significantly associated with more unfavorable outcome according to prognostic group defined by the Stage, Size, Grade, and Necrosis risk model for localized RCC. Conclusion: CMTM6 expression represents a promising prognostic biomarker in RCC, with differential associations depending on disease stage and treatment setting. Its correlation with established clinical risk classifications underscores its potential utility in prognostic refinement. Given its regulatory role in PD-L1 expression, CMTM6 may also represent a therapeutic target, with implications for optimizing immunotherapeutic strategies in RCC. Further validation in larger cohorts and prospective studies are warranted.
Tulchiner et al. (Sun,) studied this question.