Abstract 4676: Spontaneous regression of Merkel cell carcinoma is driven by adaptive immune activation and clonal T cell expansion
Authors: Baker Mairead , Roman John W. , Reuben Alexandre , Hill Natasha , Hudgens Courtney W. , Tetzlaff Michael , Logemann Nicholas F. , Brownell Isaac 
Published: August 2018

Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin tumor. MCC is immunogenic and highly responsive to immune checkpoint inhibitors. On rare occasions, MCC undergoes spontaneous regression of both local and metastatic disease in the absence of treatment. With at least 45 cases reported in the literature, this phenomenon has been described in 1.7-3% of MCCs but its mechanism is poorly understood. There has been speculation that biopsy-induced antigen shedding and subsequent recruitment of a host immune response drives spontaneous tumor regression. Here, we demonstrate activation of an adaptive immune response in a case of spontaneous MCC regression. A 65 year-old man presented with a rapidly-growing 3.5 cm skin tumor confirmed by histopathologic and immunohistochemical analyses to be Merkel cell polyomavirus-positive MCC. Eight days following the diagnostic shave biopsy, the tumor had clinically regressed. Histological analysis of a wide local excision specimen obtained 45 days after the initial biopsy revealed small, residual tumor nests and a surrounding lymphohistiocytic inflammatory infiltrate consistent with a regressing tumor. To evaluate the immune response at baseline and in the regressing tumor, we performed T cell receptor (TCR) sequencing as a metric of antigen-specific lymphocyte activation, and quantitative immunohistochemical analyses to phenotype the immune response. Both the baseline and regressing tumor contained intratumoral inflammatory infiltrates which were sparse relative to peritumoral infiltrates. There were notable reductions in CD4+ T cells and CD68+ macrophages in the regressing tumor relative to the initial biopsy. TCR clonality was increased in the regressing tumor relative to the baseline lesion, including both increased representation of the most dominant T cell clone from the baseline biopsy as well as emergence of new high-frequency clones. Together, these results suggest that spontaneous MCC regression is driven by expansion of novel and pre-existing adaptive cellular immune responses. Consistent with this, we observed analogous results with immunohistochemical staining and TCR sequencing performed in an MCC tumor regressing during treatment with the PD-L1 inhibitor, avelumab. Although further studies are needed to determine how biopsy unmasks immune responses and to elucidate target antigens of the T cell clones driving spontaneous MCC regression, our observations demonstrate that comparable immune activation underlies both spontaneous tumor regression and MCC response to immunotherapy.
Citation Format: Mairead Baker, John W. Roman, Alexandre Reuben, Natasha Hill, Courtney W. Hudgens, Michael Tetzlaff, Nicholas F. Logemann, Isaac Brownell. Spontaneous regression of Merkel cell carcinoma is driven by adaptive immune activation and clonal T cell expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4676.