Merkel Cell Polyoma Viral Load and Intratumoral CD8+ Lymphocyte Infiltration Predict Overall Survival in Patients With Merkel Cell Carcinoma

Abstract

Introduction: Merkel cell carcinoma (MCC) is linked to the presence of clonally integrated Merkel cell polyomavirus (MCPyV) in up to 80% of the cases. The aim of the study was to determine the prognostic value of baseline MCPyV viral load and lymphocytic infiltration.Methods: MCPyV DNA prevalence, integration status and viral load were determined by specific quantitative real-time PCR in surgical specimens obtained from 49 patients with MCC treated with (n = 22, 45%) or without postoperative radiotherapy (RT). CD8+ tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) status were assessed using immunohistochemistry. MCPyV characteristics and immune marker expression were correlated with clinicopathological factors and overall survival (OS).Results: Median age at diagnosis was 74 (range, 42–100); 51% of the patients were female. One-, three, and five-year OS rates were 83.8, 58.6, and 47.1%, respectively. A positive MCPyV status was associated with female gender (p = 0.042). Tumor localization (head/arms vs. trunk) positively correlated with PD-L1 status (p = 0.011) and combined CD8/PD-L1 expression (p = 0.038). Overall CD8+ infiltration was inversely associated with N-stage (p = 0.048). Stromal TILs correlated significantly with both PD-L1 expression (p = 0.010) and N-stage (p = 0.037). A high viral load (>median) was significantly associated with worse OS (p = 0.029) and high intratumoral CD8+ infiltration with improved OS for the entire cohort (p = 0.045).Conclusion: These data provide important insight on the role of MCPy DNA viral load and TILs in the context of PD-L1 in patients with Merkel cell carcinoma. Future clinical studies should aim to explore the effect of PD-1/PD-L1 immune-checkpoint inhibitors in combination with existing radiotherapy approaches.

Prognostic Role of Tumoral PD-L1 and IDO1 Expression, and Intratumoral CD8+ and FoxP3+ Lymphocyte Infiltrates in 132 Primary Cutaneous Merkel Cell Carcinomas

“…Findings reported by Micevic et al [ 15 ] suggest that the hypomethylation of PD-L1 (and possible subsequent increased protein expression of PD-L1) is associated with a phenotype of immune activation and expression of interferon signaling pathway genes in cutaneous melanoma. This hypothesis needs further investigations in MCC patients, because some studies did not confirm the significant prognostic impact of PD-L1 on survival in MCC patients [ 2 , 13 , 14 ].…”

“…Several previous studies suggest that intratumoral CD8+ lymphocytes are strongly correlated with better survival in MCC [ 2 , 3 , 4 , 28 ]. The findings of our study confirmed that high intratumoral CD8+ cell count had a positive prognostic impact on survival in MCC patients and highlighted the crucial role of cytotoxic CD8+ lymphocytes in controlling disease progression.…”

“…Etiology for MCC includes ultraviolet (UV) radiation exposure, Merkel cell polyomavirus (MCPyV) infection, and immunosuppression [ 1 ]. Although MCPyV positivity and the presence of intratumoral CD8+ lymphocytes are favorable prognostic factors [ 2 , 3 , 4 ], there remains a need for additional biomarkers to stratify MCC risk.…”

“…By blocking the interaction between PD1 and PD-L1, inhibitors such as avelumab, nivolumab, and pembrolizumab have demonstrated significant improvements in clinical responses [ 10 , 11 ]. However, prognostic significance of PD-L1 expression in MCC remains still unclear [ 2 , 12 , 13 , 14 ]. Although the intratumoral CD8+ lymphocytes have been shown to be a favorable prognostic variable, the prognostic role FoxP3+ infiltrate in MCC has not been widely studied in MCCs.…”

Merkel cell carcinoma (neuroendocrine carcinoma of the skin): a lecture with a brief overview of 19 cases and demonstration of two clinical observations

“…Однако J. von der Grün и соавт. [61] не удалось выявить существенной корреляции между инфильтрацией опухоли CD8-позитивными лимфоцитами, экспрессией в опухоли PD-L1 и вирусной нагрузкой. Авторы объясняют это тем, что иммунный ответ может зависеть от механизмов, отличных от вирусной инфекции, например, от мутаций, вызванных ультрафиолетовым излучением.…”