Low Intratumoral CD200 Protein Expression in Primary Merkel Cell Carcinoma Is a Strong Predictor for Disease Relapse

Background: Merkel cell carcinoma (MCC) is a rare and frequently fatal form of skin cancer. Apart from Programmed Cell Death Protein 1 (PD-1)/Programmed Death-Ligand 1 (PD-L1) signaling, there is a lack of knowledge regarding other immune checkpoint molecules. Recent studies have observed elevated glycoprotein CD200 (also known as OX-2) mRNA expression in in different types of tumors, with CD200R-expressing myeloid cells present in the tumor microenvironment. However, the potential role of the CD200/CD200 axis as an additional checkpoint modulator remains widely unexplored. The aim of this study was to determine the intratumoral protein expression of CD200 as well as CD200R in a larger cohort of MCC patients and to correlate the expression levels with patients’ outcomes. Methods: In this multicenter study, we investigated 68 patients with MCC (68 primary tumors and 15 corresponding metastases). Immunohistochemistry (IHC) was performed for CD200 as well as CD200R. Digital quantification and analysis of IHC were performed using QuPath-0.2.3. Results: CD200 and CD200R expression was observed in 100% of cases. Univariate analysis revealed that low CD200 expression in primary tumors (p = 0.0007, HR 9.35), male sex (p = 0.045, HR 2.41), and immunosuppression (p = 0.0031, HR 6.36) were significantly associated with MCC relapse. Low CD200 expression was also linked to prior immune checkpoint inhibitors (ICI) and/or chemotherapy treatment (p = 0.037). Multivariable analysis confirmed that low CD200 expression (p = 0.0012, HR 5.25) and immunosuppression (p = 0.0056, HR 4.11) were independent predictors of MCC relapse. Conclusions: Expression of CD200/CD200R proteins is very high in MCC and may thus be of diagnostic value. More importantly, low intratumoral CD200 protein expression in primary MCC represents a robust independent predictor of MCC relapse.