As compared to most cancers, MCC is particularly linked to immune suppression. Indeed, 7.8% of MCC patients are profoundly immune suppressed, with a 16-fold over-representation of MCC compared with the expected rate (2). Moreover, there are more than 20 reported cases of complete spontaneous regressions of confirmed MCCs often explained by a sudden immune recognition and subsequently immune-mediated clearance of this tumor (8-10). Notably, regressions may also be induced by cessation of immune suppression. Further evidence for the immunogenicity of MCC was provided by a recent study of ours: We performed an unbiased messenger RNA (mRNA) profiling approach comparing MCC tumors from patients with good and poor outcomes to reveal important aspects of MCC pathogenesis, and identify new prognostic markers. In this study, we employed transcriptome-wide mRNA profiling followed by gene set enrichment analyses to isolate factors that differentiate MCC patients with excellent clinical outcomes from those with rapidly progressive disease. In this regard, immune response-related gene signatures were prominent in cases with good prognosis. In particular, granzymes, interferon-g, and other genes associated with CD8+cytotoxic T lymphocytes (CTLs) were significantly over-expressed in MCC tumors of patients with a favorable prognosis. Immunohistochemical studies in an independent validation set confirmed the excellent survival rate in cases with a brisk intratumoral CD8+ T lymphocyte infiltration (100% MCC-specific survival, n=26) as compared to cases lacking a CD8+ intratumoral infiltrate (60% survival, n=120). Thus, a strong inflammatory infiltrate, particularly CD8+ T cells, within the tumor is associated with a favorable prognosis in MCC patients. This finding sustains the hypothesis that prognosis of MCC can be improved by immunotherapy.
The recently recognized viral pathogenesis of MCC certainly contributes largely to MCC’s high immunogenicity. In 2008, Feng et al. demonstrated the integration of viral DNA of a new polyomavirus in MCC (11); the virus was therefore named Merkel cell polyomavirus (MCV). MCV presence in MCCs has been subsequently confirmed in geographically diverse populations in about 80% of MCC cases (12). Notably, the virus integration sites vary between different MCC tumors suggesting that this event is likely to occur at random sites in the host genome. In addition, since primary and metastatic tumor samples of individual MCV-positive MCC patients exhibit an identical integration pattern, MCV integration most likely occurs before tumor metastasis. Thus, viral infection and subsequent integration seems to precede the clonal expansion of tumor cells. Recently, we demonstrated that the expression of oncogenic viral T antigens is mandatory for the maintenance of MCV-positive MCC cell lines as upon short hairpin RNA mediated knock down of T antigens MCV-positive MCC cells displayed growth arrest and apoptosis (13). This observation was the first direct experimental evidence that T antigen expression is necessary for the maintenance of MCV-positive MCC and corroborates the notion that MCV is the infectious cause of MCV-positive MCC.
We and others have recently demonstrated that virus-encoded oncoproteins are persistently expressed in ~75% of MCCs (12). As viral, non-self proteins they are highly immunogenic, and should therefore elicit cellular immune responses. Indeed, preliminary data from the consortium suggests that immunodominant T cell epitopes derived from the oncogenic virus elicit spontaneous immune responses in MCC patients. This observation explains the important impact of the host immunocompetence for the course of the disease. Notably, similar to other cancers, MCCs are endued with several means to down-modulate immune responses, e.g. by production of the immune suppressive mediator indoleamine-pyrrole 2,3-dioxygenase. Consequently, immune modulating strategies boosting the spontaneous T-cell responses by overcoming the immune escape mechanisms are particularly attractive for the therapy of MCC .