Tumor-specific T cells in human merkel cell carcinomas: A possible role for tregs and T-cell exhaustion in reducing T-cell responses

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

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1879-1889
Number of pages11
JournalJournal of Investigative Dermatology
Volume133
Issue number7
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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Merkel Cell Carcinoma
T-cells
Tumors
Cells
T-Lymphocytes
Neoplasms
Regulatory T-Lymphocytes
Skin Neoplasms
Skin
Chemical activation
Tumor-Infiltrating Lymphocytes
Interleukin-15
Polyomavirus
Lymphocytes
Macrophages
Cell culture
Grafts
Dendritic Cells
Interleukin-2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Tumor-specific T cells in human merkel cell carcinomas : A possible role for tregs and T-cell exhaustion in reducing T-cell responses. / 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.

In: Journal of Investigative Dermatology, Vol. 133, No. 7, 01.01.2013, p. 1879-1889.

Research output: Contribution to journalArticle

Dowlatshahi, M, Huang, V, Gehad, AE, Jiang, Y, Calarese, A, Teague, JE, Dorosario, AA, Cheng, J, Nghiem, P, Schanbacher, CF, Thakuria, M, Schmults, CD, Wang, LC & Clark, RA 2013, 'Tumor-specific T cells in human merkel cell carcinomas: A possible role for tregs and T-cell exhaustion in reducing T-cell responses', Journal of Investigative Dermatology, vol. 133, no. 7, pp. 1879-1889. https://doi.org/10.1038/jid.2013.75
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. / Tumor-specific T cells in human merkel cell carcinomas : A possible role for tregs and T-cell exhaustion in reducing T-cell responses. In: Journal of Investigative Dermatology. 2013 ; Vol. 133, No. 7. pp. 1879-1889.
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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.",
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AU - Huang, Victor

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AU - Jiang, Ying

AU - Calarese, Adam

AU - Teague, Jessica E.

AU - Dorosario, Andrew A.

AU - Cheng, Jingwei

AU - Nghiem, Paul

AU - Schanbacher, Carl F.

AU - Thakuria, Manisha

AU - Schmults, Chrysalyne D.

AU - Wang, Linda C.

AU - Clark, Rachael A.

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AB - 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.

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