Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma

Abstract

Purpose Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes. Experimental Design IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm2) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs. Results No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3+ (P = 0.004) and CD8+ (P = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8+ T-cell density at the tumor periphery associated with improved DSS (P = 0.049). Stratifying MCCs according to MCPyV status, higher CD3+ (P = 0.026) and CD8+ (P = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV+ but not MCPyV− MCC. TCRseq revealed clonal overlap among MCPyV+ samples, suggesting an antigen-specific response against a unifying antigen. Conclusions These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC.

S2k guidelines for Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) – update 2018

“…Histologische Charakteristika mit einer prognostischen Bedeutung sind die Tumordicke und die An-bzw. Abwesenheit von tumorinfiltrierenden Lymphozyten, insbesondere CD8 + -T-Zellen [26][27][28]. Die Wertigkeit des histologischen Subtyps (trabekulär, kleinzellig, intermediär) sowie des molekularbiologischen oder immunhistochemischen Nachweises des Merkelzellpolyomavirus für die Abschätzung der Prognose wird aktuell noch kontrovers diskutiert [29,30].…”

“…Retrospective studies have shown the following clinical features to be associated with an unfavorable prognosis: advanced tumor stage, male gender, primary tumor in the head/neck region or on the trunk, and immunosuppression. Histological characteristics of prognostic significance include tumor thickness and the presence or absence of tumor‐infiltrating lymphocytes, especially CD8 + T cells . The prognostic significance of the histological subtype (trabecular, small‐cell, intermediate) and the molecular or immunohistochemical detection of the Merkel cell polyomavirus continues to be the subject of controversial debate .…”

Gene expression profiling of lichenoid dermatitis immune‐related adverse event from immune checkpoint inhibitors reveals increased CD14+ and CD16+ monocytes driving an innate immune response

“…The total area of tissue containing inflammatory cells was designated by a dermatopathologist and IHC cells were quantified using Aperio image scope. The percentage of positive cells and H‐Score (intensity of staining [1+, 2+, 3+] x % of positive cells with that staining intensity for each marker were recorded by digital image analysis, as previously described …”

S2k‐Leitlinie Merkelzellkarzinom (MZK, MCC, neuroendokrines Karzinom der Haut) – Update 2018

“…Histologische Charakteristika mit einer prognostischen Bedeutung sind die Tumordicke und die An‐ bzw. Abwesenheit von tumorinfiltrierenden Lymphozyten, insbesondere CD8 + ‐T‐Zellen . Die Wertigkeit des histologischen Subtyps (trabekulär, kleinzellig, intermediär) sowie des molekularbiologischen oder immunhistochemischen Nachweises des Merkelzellpolyomavirus für die Abschätzung der Prognose wird aktuell noch kontrovers diskutiert .…”