Clonal T cell expansion drives spontaneous tumor regression in Merkel cell carcinoma

Authors

• PH Hallaert
• M Baker
• JM Roman
• A Reuben
• N Hill
• CW Hudgens
• MT Tetzlaff
• NF Logemann
• I Brownell

Abstract

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer that is highly responsive to immune checkpoint inhibitors (ICI). Rarely, MCC tumors can spontaneously regress without treatment. Although this phenomenon has been reported over fifty times in the literature, the mechanisms governing spontaneous regression remain poorly understood. Here, we explore the immune changes that occurred in an MCC tumor that regressed spontaneously after a diagnostic shave biopsy. Using immunohistochemical staining and quantitative spatial immune phenotyping, we found that both the baseline and regressed 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 regressed tumor relative to the initial biopsy. Compared to baseline, composition of the immune infiltrates was consistent with an activated cellular immune response, with the regressed tumor having increased proportions of cytotoxic CD8+ T cells accompanied by relative increases in immunosuppressive macrophages and regulatory T cells. To further assess this immune response, we performed T cell receptor (TCR) sequencing. Relative to baseline, the regressed tumor was associated with an overall increase in TCR clonality, expansion of maximum-frequency TCR clones, and the emergence of new high-yield clones. Comparable results were observed in an MCC tumor that regressed following treatment with avelumab, and ICI. Together, these results suggest that spontaneous regression is driven by novel and pre-existing adaptive T cell immune responses and that these polyclonal cellular responses are analogous to those observed with ICI-mediated tumor regression.

Scientific Focus Area: Cancer Biology

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