Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

Abstract

Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer that is typically caused by the Merkel cell polyomavirus (MCPyV). Polyomavirus T-antigen oncoproteins are persistently expressed in virus-positive MCCs (∼80% of cases), while remarkably high numbers of tumor-associated neoantigens are detected in virusnegative MCCs, suggesting that both MCC subsets may be immunogenic. Here we review mechanisms by which these immunogenic tumors evade multiple levels of host immunity. Additionally, we summarize the exciting potential of diverse immunebased approaches to treat MCC. In particular, agents blocking the PD-1 axis have yielded strikingly high response rates in MCC as compared with other solid tumors, highlighting the potential for immune-mediated treatment of this disease.

Merkel Cell Carcinoma: An Unusually Immunogenic Cancer Proves Ripe for Immune Therapy

“…2 Cytotoxic chemotherapy can mediate regression of distant metastatic disease in . 50% of cases; however, median time to progression is only 3 months, which indicates an urgent need for alternative approaches.…”

“…2 Of note, these responses are largely limited to local disease control and have typically not shown benefit at untreated lesions.…”

“…50 years), and extensive prior sun exposure. 2 Within the past year, multiple independent sequencing studies have revealed that MCC can be caused either by the Merkel cell polyomavirus (MCPyV) or by heavy UV exposure. 3 In most cases of MCC (approximately 80%), MCPyV is clonally integrated in MCC tumor cells and viral oncoproteins drive oncogenesis.…”

“…3 In most cases of MCC (approximately 80%), MCPyV is clonally integrated in MCC tumor cells and viral oncoproteins drive oncogenesis. 2 The remaining approximately 20% of cases are not associated with MCPyV and seem to be mediated by UV damage, as wholeexome sequencing has revealed that these tumors harbor dramatically high mutational burdens with a distinct UV damage signature. 3 In Australia, with its heavy UV exposure and predominantly white population, this ratio is inverted: the majority of MCC tumors (approximately 75%) are UV induced and MCPyV negative.…”

“…4 Importantly, while immune recognition of MCCs can be detected, several mechanisms of immune evasion, including major histocompatibility complex-I and E-selectin downregulation, T regulatory cell recruitment, impaired natural killer cell function, and decreased Toll-like receptor-9 signaling, can dampen both innate and adaptive immune responses against MCC. 2 Therapies that target these evasion mechanisms are underway and several have shown dramatic clinical results as detailed below.…”