Tumor-specific T cells in human Merkel cell carcinomas: a possible role for Tregs and T-cell exhaustion in reducing T-cell responses.

Publication Type:

Journal Article

Source:

The Journal of investigative dermatology, Volume 133, Issue 7, p.1879-89 (2013)

Keywords:

2013, Animals, Antigens, CD, Antigens, CD8, Antigens, Differentiation, T-Lymphocyte, August 2013, Carcinoma, Merkel Cell, Carcinoma, Squamous Cell, Cell Proliferation, Cells, Cultured, Center-Authored Paper, Clinical Research Division, Cytokines, Experimental Histopathology Core Facility, Forkhead Transcription Factors, Humans, Interleukin-15, Interleukin-2, Interleukin-2 Receptor alpha Subunit, Lectins, C-Type, MICE, Mice, Inbred NOD, Mice, SCID, Programmed Cell Death 1 Receptor, Signal Transduction, Skin, Skin Neoplasms, T-Lymphocytes, T-Lymphocytes, Regulatory, Transplantation, Heterologous

Abstract:

Merkel cell carcinomas (MCCs) are rare but highly malignant skin cancers associated with a recently described polyomavirus. MCC tumors were infiltrated by T cells, including effector, central memory, and 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 mice failed to grow unless human T cells in the tumor grafts were depleted with denileukin diftitox, suggesting that tumor-specific T cells capable of controlling tumor growth were present in MCC. Both CD4(+) and CD8(+) FOXP3(+) regulatory T cells were frequent in MCC. Fifty percent of nonactivated 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 regulatory T cell function, or inhibit PD-1 signaling may be effective in the treatment of this highly malignant skin cancer.