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

## TL;DR

Low CD200 protein in Merkel cell carcinoma tumors strongly predicts cancer relapse, offering a new tool for treatment planning.

## Contribution

Identifies low CD200 expression as a novel independent predictor of relapse in Merkel cell carcinoma.

## Key findings

- Low CD200 expression in primary tumors is strongly linked to higher relapse risk (HR 5.25).
- CD200 and CD200R are highly expressed in all Merkel cell carcinoma cases.
- Immunosuppressed patients face a fourfold increased risk of relapse.

## Abstract

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. This study investigated the role of the immune-related proteins CD200 and CD200R in MCC. All tumors showed high expression of these proteins, but multivariable analysis revealed two key factors independently associated with a higher risk of cancer relapse: low CD200 expression and patient immunosuppression. Specifically, patients with low CD200 expression were over five times more likely to experience relapse, while immunosuppressed individuals had a fourfold increased risk. These results highlight the potential of CD200 as a predictive marker for MCC recurrence, which could help guide future treatment strategies.

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.