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

Piotr Donizy,Mai P. Hoang,Przemyslaw Biecek,Malgorzata Pieniazek,Janusz Ryś,Cheng-Lin Wu,Janusz Kopczynski

doi:10.3390/ijms22115489

Abstract

The association of immune markers and clinicopathologic features and patient outcome has not been extensively studied in Merkel cell carcinoma (MCC). We correlated tumoral PD-L1 and IDO1 expression, and intratumoral CD8+ and FoxP3+ lymphocytes count with clinicopathologic variables, Merkel cell polyomavirus (MCPyV) status, and patient outcomes in a series of 132 MCC. By univariate analyses, tumoral PD-L1 expression >1% and combined tumoral PD-L1 >1% and high intratumoral FoxP3+ lymphocyte count correlated with improved overall survival (OS) (p = 0.016, 0.0072), MCC-specific survival (MSS) (p = 0.019, 0.017), and progression-free survival (PFS) (p = 0.043, 0.004, respectively). High intratumoral CD8+ and FoxP3+ lymphocyte count correlated with longer MSS (p = 0.036) and improved PFS (p = 0.047), respectively. Ulceration correlated with worse OS and worse MSS. Age, male gender, and higher stage (3 and 4) significantly correlated with worse survival. MCPyV positivity correlated with immune response. By multivariate analyses, only ulceration and age remained as independent predictors of worse OS; gender and stage remained for shorter PFS. Tumoral PD-L1 expression and increased density of intratumoral CD8+ lymphocytes and FoxP+ lymphocytes may represent favorable prognosticators in a subset of MCCs. Tumoral PD-L1 expression correlated with intratumoral CD8+ and FoxP3+ lymphocytes, which is supportive of an adaptive immune response.

Highlights

Tumoral IDO1 expression can be variable in various cancers [7,8], and its expression in Merkel cell carcinoma (MCC) has been reported in only one prior study where its high expression correlated with unfavorable clinical outcome [9]
We observed tumoral PD-L1 expression in Merkel cell polyomavirus (MCPyV)-positive tumors more frequently than MCPyV-negative MCCs (48 versus 16, p = 0.018) in our series, supporting the hypothesis that virus-positive and virus-negative MCCs have different immune microenvironment. These findings suggest that MCPyV-related immune response upregulates tumoral PD-L1 and tumoral IDO1 expression and intratumoral CD8+ infiltrate
Tumoral PDL1 expression and increased density of intratumoral CD8+ lymphocytes and FoxP3+ lymphocytes may positively impact on survival in a subset of MCCs

Summary

Introduction

Merkel cell carcinoma (MCC) is a rare and aggressive primary cutaneous neuroendocrine carcinoma with frequent recurrences, metastases, high mortality rates, and rapidly increasing reported incidence [1]. Etiology for MCC includes ultraviolet (UV) radiation exposure, Merkel cell polyomavirus (MCPyV) infection, and immunosuppression [1]. IDO1 is an intracellular cytoplasmic enzyme that catalyzes the degradation of tryptophan to kynurenine pathway metabolites [5]. The deregulation of tryptophan metabolism (decreasing tryptophan and increasing tryptophan metabolites) is connected with induction of the cell-cycle arrest and effector T-cell apoptosis and promotes Tregs activity, contributing to local immunosuppression [6]. Tumoral IDO1 expression can be variable in various cancers [7,8], and its expression in MCC has been reported in only one prior study where its high expression correlated with unfavorable clinical outcome [9]

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