title: Tumor-specific T cells in human Merkel cell carcinomas: a possible role for Tregs and T-cell exhaustion in reducing T-cell responses.
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.
authors: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors: Mitra
authors: M
authors: Dowlatshahi
authors: Victor
authors: V
authors: Huang
authors: Ahmed E
authors: AE
authors: Gehad
authors: Ying
authors: Y
authors: Jiang
authors: Adam
authors: A
authors: Calarese
authors: Jessica E
authors: JE
authors: Teague
authors: Andrew A
authors: AA
authors: Dorosario
authors: Jingwei
authors: J
authors: Cheng
authors: Paul
authors: P
authors: Nghiem
authors: Carl F
authors: CF
authors: Schanbacher
authors: Manisha
authors: M
authors: Thakuria
authors: Chrysalyne D
authors: CD
authors: Schmults
authors: Linda C
authors: LC
authors: Wang
authors: Rachael A
authors: RA
authors: Clark
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D015266:Carcinoma, Merkel Cell / Q000378:metabolism / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology*; D014183:Transplantation, Heterologous; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016827:CD8 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D061026:Programmed Cell Death 1 Receptor; D000099192:CD69 Antigens; C418974:FOXP3 protein, human; C105992:PDCD1 protein, human