Tumor-Specific T Cells in Human Merkel Cell Carcinomas: A Possible Role for Tregs and T-Cell Exhaustion in Reducing T-Cell Responses

Academic Article


  • 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.
  • Authors

  • Dowlatshahi, Mitra
  • Huang, Victor
  • Gehad, Ahmed E
  • Jiang, Ying
  • Calarese, Adam
  • Teague, Jessica E
  • Dorosario, Andrew A
  • Cheng, Jingwei
  • Nghiem, Paul
  • Schanbacher, Carl F
  • Thakuria, Manisha
  • Schmults, Chrysalyne D
  • Wang, Linda C
  • Clark, Rachael A
  • Status

    Publication Date

  • July 2013
  • Published In


  • Animals Antigens, CD/metabolism Antigens, CD8/metabolism Antigens, Differentiation, T-Lymphocyte/metabolism Carcinoma, Merkel Cell/metabolism/*pathology Carcinoma, Squamous Cell/metabolism/pathology Cell Proliferation/drug effects Cells, Cultured Cytokines/metabolism Forkhead Transcription Factors/metabolism Humans In Vitro Techniques Interleukin-15/pharmacology Interleukin-2/pharmacology Interleukin-2 Receptor alpha Subunit/metabolism Lectins, C-Type/metabolism Mice Mice, Inbred NOD Mice, SCID Programmed Cell Death 1 Receptor/*metabolism Signal Transduction/physiology Skin/metabolism/pathology Skin Neoplasms/metabolism/*pathology T-Lymphocytes/drug effects/*metabolism/*pathology T-Lymphocytes, Regulatory/*metabolism/*pathology Transplantation, Heterologous
  • Digital Object Identifier (doi)

    Start Page

  • 1879
  • End Page

  • 1889
  • Volume

  • 133
  • Issue

  • 7