As outlined above, MCC is a cancer whose clinical course is largely influenced by the host’s immune system. Over the past years, it became obvious that the competence of the host to mount an immune response is influenced by several factors. One of these is the genetic predisposition which can be reconnoitered by analyzing single nucleotide polymorphisms in immune response genes (43). Moreover, MCC is characterized by several means of escaping these immune responses. For example, the draining lymph nodes, i.e. the sentinel lymph nodes, of primary MCCs are characterized by an immune suppressed state as substantiated by the predominance of immature dendritic cells. However, the mechanism of this immune suppression remains largely elusive.
Comparison of the maturation status of dendritic cells in the draining lymph node of a Merkel cell carcinoma and a melanoma. Lack of dendrites and lower expression of maturation markers such as CD80 and CD86 suggest an immune suppressed state in the MCC patient.
Previous trials of immunotherapy of cancer unequivocally demonstrated the feasibility of therapeutic induction of tumor-specific immune responses, at least those measured in the circulating blood. The clinical benefit of the majority of these trials, however, was very limited (44). The discussed reasons for this gap are immune escape mechanisms of the tumor, impaired homing of induced T cells to the tumor site, or negative regulatory circuits impairing the induced immune response. By detailed comparative analysis of patients treated by F16-IL2 administration within IMMOMEC mounting systemic immune responses but experiencing either a clinical benefit or not we will establish the etiological factors governing whether a systemic MCC-specific T-cell response is able to eradicate the tumor. A special focus will be the in situ analysis of regressing and non-regressing MCC lesions; such an analysis is possible by taking advantage of a recently developed in situ staining of antigen specific T-cell receptors using multimeric peptide-MHC class I complexes which allows the functional characterization of antigen specific T cells in the tumor microenvironment (45). This improved understanding of cancer immunology will subsequently be conveyed to other immunotherapy trials of cancer using targeted cytokine therapy, e.g. L19-IL2 in melanoma, immunomodulatory antibodies such as ipilimumab, or vaccination strategies.
