Merkel cell polyomavirus-specific T cell responses, immune evasion mechanisms & immune therapy in Merkel cell carcinoma
Afanasiev, Olga Kochan
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Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with an increasing incidence and a 5-year disease-associated mortality of 46%. The Merkel cell polyomavirus (MCPyV), discovered in 2008, is involved in the pathogenesis of over 80% of MCC tumors. MCC typically requires persistent expression of immunogenic polyomavirus tumor-antigen (T-Ag) oncoproteins for growth and survival. We have found that these viral oncoproteins elicit T cell immune responses that specifically target virus-driven MCC tumors. Furthermore, in individual patients, these MCC-specific T cells in the blood increase with MCC disease progression and decrease with effective disease therapy. The presence of these tumor-targeting T cells in patients with MCC tumors suggested there may be several immune evasion mechanisms that prevent adequate immune control of this cancer. We first characterized the molecular pathways involved in inhibiting protective T cell immune responses. To assess the functional state of MCC-specific CD8 T cells, we determined the expression of physiologically relevant cell surface markers and cytokine production directly ex vivo. MCC-specific T cells fail to produce activation cytokines in response to the viral oncoproteins and they co-express PD-1 and Tim-3 inhibitory receptors, a phenotype strongly associated with T cell exhaustion and dysfunction. Importantly, these inhibitor pathways can be therapeutically targeted using existing or emerging agents to augment T cell function. Previous studies identified that high levels of CD8 lymphocytes within the tumor are strongly correlated with improved survival, although these cells are absent or sparse in ~80% of MCCs. We investigated specific mechanisms that may prevent adequate T cell infiltration into MCC tumors. We found that intratumoral vascular E-selectin, critical for T cell recruitment and entry into skin, was downregulated in the majority (52%) of MCCs, which was associated with poor intratumoral CD8 lymphocyte infiltration and poorer survival. We have also identified that human leukocyte antigen class I (HLA-I) is downregulated in the majority (51%) of MCC tumors, which suppresses antigen presentation, thus promoting evasion of CD8 T cell responses. Excitingly, these findings have resulted in significant translational applications. Specifically, we have treated a patient with metastatic MCC by using an innovative therapeutic combination of polyclonal, tumor-specific cytotoxic T cells infused following a pre-conditioning regimen (interferon-beta or radiotherapy) that reverses local tumor immune evasion mechanisms. This combination resulted in the elimination of 2 of 3 metastatic tumors and yielded a distant metastasis free survival of 535 days, far beyond expected among such patients (95% CI: 154-260 days). Immunologic responses included persistence of MCPyV-specific T cells at several-fold above baseline and improved antigen-specific T cell responses that persisted beyond 100 days after treatment. Importantly, this therapy was well tolerated without significant side effects. In summary, these studies have characterized the cellular immune responses in MCC and have identified several immune evasion pathways that may be therapeutically targeted to augment the efficacy of immune therapy in MCC.
- Pathology