Merkel cell polyomavirus-specific immune responses in patients with Merkel cell carcinoma receiving anti-PD-1 therapy

Natalie J Miller,Steven P Fling,Rima Kulikauskas,Martin A Cheever,Michi M Shinohara,Paul Nghiem,Candice D Church,Harriet M Kluger,Lisa Lundgren,Nirasha Ramchurren,Shailender Bhatia,Suzanne L Topalian

doi:10.1186/s40425-018-0450-7

Abstract

BackgroundMerkel cell carcinoma (MCC) is an aggressive skin cancer that frequently responds to anti-PD-1 therapy. MCC is associated with sun exposure and, in 80% of cases, Merkel cell polyomavirus (MCPyV). MCPyV-specific T and B cell responses provide a unique opportunity to study cancer-specific immunity throughout PD-1 blockade therapy.MethodsImmune responses were assessed in patients (n = 26) with advanced MCC receiving pembrolizumab. Peripheral blood mononuclear cells (PBMC) were collected at baseline and throughout treatment. MCPyV-oncoprotein antibodies were quantified and T cells were assessed for MCPyV-specificity via tetramer staining and/or cytokine secretion. Pre-treatment tumor biopsies were analyzed for T cell receptor clonality.ResultsMCPyV oncoprotein antibodies were detectable in 15 of 17 (88%) of virus-positive MCC (VP-MCC) patients. Antibodies decreased in 10 of 11 (91%) patients with responding tumors. Virus-specific T cells decreased over time in patients who had a complete response, and increased in patients who had persistent disease. Tumors that were MCPyV(+) had a strikingly more clonal (less diverse) intratumoral TCR repertoire than virus-negative tumors (p = 0.0001).ConclusionsCancer-specific T and B cell responses generally track with disease burden during PD-1 blockade, in proportion to presence of antigen. Intratumoral TCR clonality was significantly greater in VP-MCC than VN-MCC tumors, suggesting expansion of a limited number of dominant clones in response to fewer immunogenic MCPyV antigens. In contrast, VN-MCC tumors had lower clonality, suggesting a diverse T cell response to numerous neoantigens. These findings reveal differences in tumor-specific immunity for VP-MCC and VN-MCC, both of which often respond to anti-PD-1 therapy.

Highlights

Merkel cell carcinoma (MCC) is an aggressive skin cancer that frequently responds to anti-progressive disease (PD)-1 therapy
We assessed whether the presence of B or T cell reactivities against Merkel cell polyomavirus (MCPyV) T-antigens in patients with virus-positive MCC (VP-MCC) correlated with clinical outcomes
Peripheral blood mononuclear cells (PBMC) that secreted interferon-gamma and/or Interleukin 2 (IL-2) robustly (≥0.1% of CD8 T cells after background subtraction) were considered reactive to MCPyV d Abbreviations for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria are as follows: CR complete response, PR partial response, PD progressive disease and T cell reactivities to MCPyV T-antigens were not found in patients with Virus-negative Merkel cell carcinoma (VN-MCC) tumors

Summary

Introduction

Merkel cell carcinoma (MCC) is an aggressive skin cancer that frequently responds to anti-PD-1 therapy. The majority of MCCs are driven by the Merkel cell polyomavirus (MCPyV) T-antigen oncoproteins, while the remaining MCCs are ‘virus-negative’, and are driven by UV-induced mutagenesis [1,2,3]. Both virus-positive (VP) and virus-negative (VN) MCC are immunogenic and can elicit MCC-specific CD8+ and CD4+ T cell responses [4, 5], and most patients with VP-MCC mount a B cell response against the MCPyV T-antigen oncoproteins [6, 7]. To date there are no clear clinical or tumor characteristics that can predict which patients are more likely to respond [11, 12] and the mechanisms of response and resistance are poorly understood

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