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Importantly, proper assessment of therapeutic efficacy or failure requires that serial tumor biopsies be obtained from both before and after immune therapy, despite their high costs and logistical challenges

Importantly, proper assessment of therapeutic efficacy or failure requires that serial tumor biopsies be obtained from both before and after immune therapy, despite their high costs and logistical challenges. led to major changes in advanced MCC therapy, including the first-ever FDA drug approval for this disease. Despite these successes, 50% of MCC patients do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden anti-tumor immune responses in these patients. Here we spotlight recent progress in MCC including the underlying mechanisms of immune evasion and emerging approaches to augment the efficacy of PD-1 pathway blockade. (18,20,22), however numerous attempts to generate mouse models of MCC at best only partially emulate the disease in adult animals (23-25). The data indicate that additional, as yet undetermined factors are required for induction of MCPyV-associated MCC. While several groups have successfully generated xenografts using MCC cell lines and transfer of postoperative tumor tissue, engraftment can only be done in NOD SCID IL2Rgamma-/- (NSG) mice, which have a severely impaired immune system. These xenograft models mimic the gross pathological features of the corresponding patient’s tumor but fail to recapitulate the tumor-immune interactions that are now understood greatly affect patient outcomes. experiments have demonstrated that ongoing expression of MCPyV oncoproteins is required for survival of virus-positive MCC cells (26-28). These persistently expressed non-self-antigens can potently elicit host immune recognition and the limited size of MCPyV T-antigens( 400 amino acids) has facilitated immune studies of MCPyV-specific T cell responses (29-32). Open in a separate window Physique 2 Comparison of virus-positive and virus-negative MCC tumorsThis schematic depicts the two major causes of MCC, their prevalence, differences in their potential immune targets, and frequencies of response to immune therapy. Top: Differences in MCC prevalence C US/Europe vs. Australia. Left: Virus-induced tumorigenesis C The highly prevalent Merkel cell polyomavirus (MCPyV) is usually often found on normal skin. Rarely, MCPyV GSK583 will integrate into the host genome and through a separate rare event, large T will become truncated (tLT; depicted by red X’s) prior its C-terminal. Expresssion of the sT and tLT viral oncogenes is usually tumorigenic through multiple pathways including inhibition of wild-type cellular Rb (see text). Right: UV-induced tumorigenesis C Sun exposure results in the generation of many UV-signature mutations (C- T mutations). The most common of which are in and includes both activating and inactivating mutations. Recommendations (16, 18-21, 40-43, 71-75) Antibodies to MCPyV T antigen correlate with tumor burden The strong response to MCPyV-positive tumors can include both T cell and humoral components (33-35). At the time of diagnosis, approximately half of MCC patients make antibodies to MCPyV-oncoproteins. Knowing a patient’s sero-status (MCPyV-positive or unfavorable) can be helpful for their subsequent care. The prognosis of seronegative patients is usually less favorable (42% higher GSK583 risk of recurrence than sero-positive patients) (35,36) and thus need to be followed closely with scans (36). For sero-positive patients antibody titers correlate with tumor burden (33,34), and a rising titer is an early indicator of disease recurrence (33). These GSK583 findings have recently been validated in a large prospective cohort (36) and the test is now included in the 2018 National Comprehensive Malignancy GSK583 Network (NCCN) guidelines for MCC (37). Effective surveillance is relevant to patient care because if disease recurrence is usually discovered early (when tumor burden is lower), immunotherapy may be GSK583 more effective (38). UV-induced MCC Some MCC tumors have no MCPyV detectable by either DNA-PCR or immunohistochemistry, which raised the question of whether Cspg2 virus-negative MCC exists or whether viral detection techniques were insufficient (39). Recent studies have exhibited that MCPyV-negative MCC tumors do indeed exist, with variable incidence.