Suppressed Activity of Tumor-Specific T Cells in Human Merkel Cell Carcinomas

Abstract

Merkel cell carcinomas (MCC) are rare but highly malignant skin cancers associated with a novel polyomavirus. We studied T cells in MCC to determine how these virally mediated tumors evade immune responses. MCC tumors were infiltrated by T cells, including effector, central memory and increased numbers of CD4 and CD8 FOXP3+ regulatory T cells. Infiltrating T cells showed markedly reduced activation as evidenced by reduced expression of CD69 and CD25. Treatment of MCC tumors in vitro with IL-2 and IL-15 led to T cell activation, proliferation, enhanced cytokine production and loss of viable tumor cells from cultures. Expanded tumor-infiltrating lymphocytes showed TCR repertoire skewing and upregulation of CD137. MCC tumors implanted into immunodeficient NOD/SCID/IL2 receptor g chainnull mice failed to grow unless human T cells in the tumor grafts were depleted with denileukin diftitox, suggesting tumor-specific T cells capable of controlling tumor growth were present in MCC. 50% of non-activated T cells in MCC expressed PD-1, a marker of T cell exhaustion, and PD-L1 and PD-L2 were expressed by a subset of tumor dendritic cells and macrophages. In summary, we observed tumor-specific T cells with suppressed activity in MCC tumors. Agents that stimulate T cell activity, block Treg function or inhibit PD-1 signaling may be effective in the treatment of this highly malignant skin cancer.