Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity
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Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity. / Donia, Marco; Andersen, Rikke; Kjeldsen, Julie W; Fagone, Paolo; Munir, Shamaila; Nicoletti, Ferdinando; Andersen, Mads Hald; Thor Straten, Per; Svane, Inge Marie.
I: Cancer Research, Bind 75, Nr. 18, 15.09.2015, s. 3747-59.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity
AU - Donia, Marco
AU - Andersen, Rikke
AU - Kjeldsen, Julie W
AU - Fagone, Paolo
AU - Munir, Shamaila
AU - Nicoletti, Ferdinando
AU - Andersen, Mads Hald
AU - Thor Straten, Per
AU - Svane, Inge Marie
N1 - ©2015 American Association for Cancer Research.
PY - 2015/9/15
Y1 - 2015/9/15
N2 - In the absence of a local inflammatory response, expression of MHC class II molecules is restricted mainly to hematopoietic cells and thymus epithelium. However, certain tumors, such as melanoma, may acquire aberrant constitutive expression of MHC class II. In a set of primary melanoma cell populations and correspondingly expanded autologous tumor-infiltrating lymphocytes (TIL), we show how MHC class II expression on melanoma cells associates with strong MHC class II-restricted CD4(+) T-cell responses that are specific for tumors. Notably, we found that tumor-specific CD4(+) T-cell responses were dominated by TNF production. TNF reduced CD8(+) T-cell activation in IFNγ-rich environments resembling a tumor site. Conversely, direct CD4(+) T-cell responses had no influence on either the proliferation or viability of melanoma cells. Taken together, our results illustrate a novel immune escape mechanism that can be activated by aberrant expression of MHC class II molecules, which by attracting tumor-specific CD4(+) T cells elicit a local inflammatory response dominated by TNF that, in turn, inhibits cytotoxic CD8(+) T-cell responses
AB - In the absence of a local inflammatory response, expression of MHC class II molecules is restricted mainly to hematopoietic cells and thymus epithelium. However, certain tumors, such as melanoma, may acquire aberrant constitutive expression of MHC class II. In a set of primary melanoma cell populations and correspondingly expanded autologous tumor-infiltrating lymphocytes (TIL), we show how MHC class II expression on melanoma cells associates with strong MHC class II-restricted CD4(+) T-cell responses that are specific for tumors. Notably, we found that tumor-specific CD4(+) T-cell responses were dominated by TNF production. TNF reduced CD8(+) T-cell activation in IFNγ-rich environments resembling a tumor site. Conversely, direct CD4(+) T-cell responses had no influence on either the proliferation or viability of melanoma cells. Taken together, our results illustrate a novel immune escape mechanism that can be activated by aberrant expression of MHC class II molecules, which by attracting tumor-specific CD4(+) T cells elicit a local inflammatory response dominated by TNF that, in turn, inhibits cytotoxic CD8(+) T-cell responses
KW - Antigens, Neoplasm
KW - CD4-Positive T-Lymphocytes
KW - CD8-Positive T-Lymphocytes
KW - Cell Line, Tumor
KW - Chemotaxis, Leukocyte
KW - Coculture Techniques
KW - Cytotoxicity, Immunologic
KW - Gene Expression Regulation, Neoplastic
KW - Genes, MHC Class II
KW - HLA-D Antigens
KW - Humans
KW - Interferon-gamma Release Tests
KW - Lymphocyte Activation
KW - Lymphocytes, Tumor-Infiltrating
KW - Melanoma
KW - T-Lymphocyte Subsets
U2 - 10.1158/0008-5472.CAN-14-2956
DO - 10.1158/0008-5472.CAN-14-2956
M3 - Journal article
C2 - 26183926
VL - 75
SP - 3747
EP - 3759
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 18
ER -
ID: 161731114