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 language | English (US) |
|---|---|
| Pages (from-to) | 1879-1889 |
| Number of pages | 11 |
| Journal | Journal of Investigative Dermatology |
| Volume | 133 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jan 1 2013 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Tumor-specific T cells in human merkel cell carcinomas
T2 - A possible role for tregs and T-cell exhaustion in reducing T-cell responses
AU - Dowlatshahi, Mitra
AU - Huang, Victor
AU - Gehad, Ahmed E.
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.
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84879414745&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879414745&partnerID=8YFLogxK
U2 - 10.1038/jid.2013.75
DO - 10.1038/jid.2013.75
M3 - Article
C2 - 23419694
AN - SCOPUS:84879414745
VL - 133
SP - 1879
EP - 1889
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 7
ER -