The biology and treatment of Merkel cell carcinoma: current understanding and research priorities

Abstract

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. Both virus-positive and virus-negative MCCs are immunogenic, and inhibition of the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) immune checkpoint has proved to be highly effective in treating patients with metastatic MCC; however, not all patients have a durable response to immunotherapy. Despite these rapid advances in the understanding and management of patients with MCC, many basic, translational and clinical research questions remain unanswered. In March 2018, an International Workshop on Merkel Cell Carcinoma Research was held at the US National Cancer Institute, at which academic, government and industry experts met to identify the highest-priority research questions. Here, we review the biology and treatment of MCC and report the consensus-based recommendations agreed upon during the workshop.

Fig. 1. Clinical and histological appearance of MCC.

a | Photograph depicting the clinical appearance of Merkel cell carcinoma (MCC), presenting as a rapidly growing nodule on an extremity; such lesions can also be commonly observed on a patient’s head or neck. b | Light micrograph (×400 magnification) of a sample stained with haematoxylin and eosin depicting the histological appearance of MCC, demonstrating the presence of round cells with scant cytoplasm, neuroendocrine chromatin and numerous mitotic figures (arrows). Trabecular patterning might also be prominent.

Fig. 2. Structure and function of the Merkel cell polyomavirus genome.

a | Merkel cell polyomavirus (MCPyV) is a small double-stranded DNA virus with a 5,387 bp circular genome that includes a non-coding control region (NCCR), an early region containing T antigen genes that coordinate viral replication and a late region containing viral protein (VP) genes for virion capsid proteins. b | Multiple transcripts are generated from the early region by alternative splicing and possibly alternative start sites, including large T antigen (LT), small T antigen (ST), 57 kT antigen (57 kT), alternative frame of the large T open reading frame (ALTO) and microRNA MCV-miR-M1. c | Cellular functions of the MCPyV LT. The DnaJ domain mediates binding to heat shock cognate 71 kDa protein, with a role in viral replication. The MCPyV unique region (MUR) includes the retinoblastoma-associated protein (RB) binding motif responsible for direct inhibition of RB, thus enabling cell cycle progression to S phase. The MUR mediates binding to the vacuolar sorting protein VPS39. The carboxyl-terminal helicase domain is a critical mediator of viral replication, with contributions from the adjacent zinc-finger (ZN), leucine zipper (LZ) and origin binding domain (OBD). The integrated MCPyV genome present in MCPyV-positive MCCs harbours truncating mutations in LT that disrupt the helicase domain, resulting in a replication-incompetent mutant form of LT that nonetheless retains the ability to promote cell cycle progression. d | Cellular functions of MCPyV ST. ST recruits L-MYC to the EP400 chromatin remodelling complex in order to mediate changes in gene expression. The LT-stabilizing domain (LSD) is proposed to inhibit E3 ubiquitin ligase activity via interactions with F-box/WD repeat-containing protein 7 (FBXW7) and cell division cycle protein 20 homologue (CDC20), resulting in increased oncoprotein stability and cap-dependent mRNA translation, respectively. ST also interacts with the protein phosphatase complex PP4 to inhibit nuclear factor-κB (NF-κB) signalling. 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; CR1, conserved region 1; NEMO, NF-κB essential modulator; NLS, nuclear localization signal.

Fig. 3. Proposed MCC tumorigenesis pathways in the presence or absence of Merkel cell polyomavirus.

a | In virus-negative Merkel cell carcinomas (VN-MCCs), the cell of origin undergoes ultraviolet-mediated DNA damage, resulting in a high tumour mutational burden and inactivation of tumour suppressor genes, including RB1 and TP53. The high mutational burden might result in the expression of tumour neoantigens that represent potential targets for antitumour immunity. b | In virus-positive MCC (VP-MCC), the cell of origin is infected by wild-type Merkel cell polyomavirus (MCPyV), which undergoes episomal replication. Rarely, MCPyV can become integrated into the host cell genome and further acquires a truncating mutation of the large T antigen (LT), resulting in deficient viral replication with continued production of viral oncoproteins. The resulting tumour has a low burden of cellular genomic mutations. Hence, for patients with VP-MCCs, T antigen proteins (rather than neoantigens) might be better targets for treatments designed to promote antitumour immunity.

Fig. 4. Signalling pathways that modulate antitumour immunity.

Antitumour immunity is modulated by signalling molecules expressed on immune cells, including T cells and antigen-presenting cells (APCs), as well as Merkel cell carcinoma (MCC) cells. Adaptive antitumour immunity is primarily mediated by the presentation of tumour antigens on MHCs of either tumour cells or APCs. In the context of MCC, tumour-associated antigens can be either viral protein products in Merkel cell polyomavirus (MCPyV)-positive MCC or, in MCPyV-negative tumours, neoantigens resulting from somatic mutations. In virus-positive-MCC tumour cells, antigen presentation by MHC complexes is commonly suppressed through epigenetic silencing. Multiple signalling pathways have the potential to either stimulate (such as OX40–OX40L) or suppress antitumour immunity (such as programmed cell death protein 1 (PD-1)– programmed cell death protein 1 ligand 1 (PD-L1)). These various immune signalling pathways should be considered potential therapeutic targets. CTLA-4, cytotoxic T antigen 4; GITR, glucocorticoid-induced TNFR-related protein; SIRP α, signal-regulatory protein α; TCR, T cell receptor.