Merkel cell polyomavirus is a recently described polyomavirus (2
) and MCPyV T-antigen oncoproteins are persistently expressed in MCC tumors (7
). These oncoproteins are capable of eliciting a humoral immune response, they are more prevalent and of higher titer in MCC cases than controls. Furthermore, there is a strong association between T-Ag antibodies and virus detection in the MCC tumor. Finally, antibodies to MCPyV T-Ag oncoprotein (but not MCPyV capsid) vary greatly over time in MCC patients and reflect the burden of disease.
The strong association between antibodies to MCPyV T-Ags and Merkel cell carcinoma is similar to prior VP1 studies in this cancer in their support of a link between MCPyV and MCC and the concept that Merkel cell carcinoma patients have long-term, high-level and/or recent exposure to Merkel cell polyomavirus antigens (11
). Furthermore, and unlike anti-VP1 antibodies, T-Ag antibodies were only rarely detected among controls. This means that T-Ag antibodies are more specifically associated with Merkel cell carcinoma than antibodies to the capsid protein.
Interestingly, and in contrast to controls, MCC cases almost exclusively recognize a T-Ag epitope located in the common domain shared between MCPyV LT-Ag and ST-Ag, whereas the rare seropositive population controls usually recognized epitopes unique to LT-Ag. We hypothesize that large T reactive controls may represent cross-reactions to a different protein.
MCC patients with detectable MCPyV in their tumor by PCR or IHC were more likely to have anti-VP1 and anti-T-Ag antibodies than those without detectable MCPyV. Interestingly, no case with a MCPyV negative tumor seroreacted to MCPyV T-Ag. This suggests there might be a population of MCC that develop without MCPyV involvement.
Importantly, we observed rapid changes in T-Ag titer that vacillated with disease burden. Indeed, titer often varied more than 10 fold in a one-year period. Importantly, titers were highest when patients were sickest, suggesting that antibodies to T-Ag are not protective against disease progression. Similar to our observations, in some other cancers, antibodies recognizing human cancer antigens (such as p53) or papillomavirus proteins have been reported to be volatile and change with cancer burden (25
The rapid turnover of IgG antibodies recognizing T-Ag in MCC patient sera suggests instability within the B cell population. Chemotherapy was not the cause of observed IgG decreases as no patients in had ever received chemotherapy. Instead, variation in titer is likely due to changes in antigen burden reducing or increasing stimulation of effector B lymphocytes. It is also possible that the memory B cell response is not generated properly, perhaps due to ineffective priming within the tumor microenvironment.
It is possible that tracking the antibody titer to the viral T-Ag holds promise as an MCC disease marker. Computed tomography imaging is expensive and has rather poor sensitivity and specificity for MCC (27
). In three cases, a rise in serologic ST-Ag titer preceded clinical detection of MCC metastasis by 1–6 months. For patients with a positive baseline MCPyV T-Ag titer, it may make be appropriate to follow T-Ag titer at subsequent clinic visits in order to better inform clinicians of possible occult recurrence.
Our study has several limitations. The first is that serial blood draws were only available for 20 seropositive cases. The second is that it is currently impossible to know which if any “NED” patients may have slowly growing, clinically occult MCC. A third limitation is that given the very small number of control subjects with antibodies to small T-Ag (5 of 530), our estimate of the hazard ratio associated with seropositivity to small T-Ag is imprecise.
Despite these limitations, this study represents a significant advance in our understanding of the humoral immune response to Merkel cell polyomavirus and Merkel cell carcinoma. In summary, there are striking differences between MCC cases and matched population controls in anti-MCPyV T-Ag antibody prevalence, titer, and specificity. Further study of anti-MCPyV T-Ag antibodies in an enlarged population of MCC patients is indicated to determine their potential for clinical utility in assessing disease status of this cancer.