Immunobiology of Merkel cell carcinoma: implications for immunotherapy of a polyomavirus-associated cancer

Abstract

Merkel cell carcinoma (MCC) is an aggressive skin malignancy with a high mortality rate and an increasing incidence. The recent discovery of Merkel cell polyomavirus has revolutionized our understanding of MCC pathogenesis. Viral oncoproteins appear to play a critical role in tumor progression and are expressed in the majority of MCC tumors. Virus-specific humoral and cellular immune responses are detectable in MCC patients and are linked to the natural history of the disease. Despite persistent expression of immunogenic viral proteins, however, MCC tumors are able to evade the immune system. Understanding of the mechanisms of immune evasion employed by MCC tumors is rapidly increasing and offers opportunities for development of rational immune therapies to improve patient outcomes. Here we review recent discoveries in MCC with a special focus on the pathogenic role of Merkel cell polyomavirus and the immunobiology of this virus-associated disease.

Figure 1. Although infection with MCPyV is common, a progression of several rare mutagenic events and escape from immune surveillance likely precede the development of Merkel cell carcinoma

Infection with MCPyV occurs early in childhood [30], is clinically asymptomatic and likely induces an appropriate humoral and cellular immune response. Ultraviolet (UV) radiation or other environmental mutagens may mediate virus integration into the host genome and Large T (LT)-antigen truncation mutations [44]. These sequential mutational events result in persistent T-Ag expression (brown stain with IHC anti-LT antibody, CM2B4) that plays a key role in MCC pathogenesis [26, 42, 46]. Importantly, in parallel, local, systemic or tumor induced loss of immune surveillance may allow for an unsupervised increase in both wild-type virus burden and T-Ag dependent MCC disease. Oftentimes, disease progression can be monitored via immune biomarkers such as anti-T-Ag antibody levels [60] and disease outcome can be predicted by levels of CD8 T cell infiltration [63].