TY - JOUR

T1 - TNF Receptor-2 Facilitates an Immunosuppressive Microenvironment in the Liver to Promote the Colonization and Growth of Hepatic Metastases

AU - Ham, Boram

AU - Wang, Ni

AU - D'Costa, Zarina

AU - Fernandez, Maria Celia

AU - Bourdeau, France

AU - Auguste, Patrick

AU - Illemann, Martin

AU - Eefsen, Rikke Helene Løvendahl

AU - Høyer-Hansen, Gunilla

AU - Vainer, Ben

AU - Evrard, Maximilien

AU - Gao, Zu-Hua

AU - Brodt, Pnina

N1 - ©2015 American Association for Cancer Research.

PY - 2015/12/15

Y1 - 2015/12/15

N2 - Successful colonization by a cancer cell of a distant metastatic site requires immune escape in the new microenvironment. TNF signaling has been implicated broadly in the suppression of immune surveillance that prevents colonization at the metastatic site and therefore must be blocked. In this study, we explored how TNF signaling influences the efficiency of liver metastasis by colon and lung carcinoma in mice that are genetically deficient for the TNF receptor TNFR2. We found a marked reduction in liver metastases that correlated with a greatly reduced accumulation at metastatic sites of CD11b(+)GR-1(+) myeloid cells with enhanced arginase activity, identified as myeloid-derived suppressor cells (MDSC). Reduced infiltration of MDSC coincided with a reduction in the number of CD4(+)FoxP3(+) T regulatory cells in the tumors. Reconstitution of TNFR2-deficient mice with normal bone marrow, or adoptive transfer of TNFR2-expressing MDSC into these mice, was sufficient to restore liver metastasis to levels in wild-type mice. Conversely, treatment with TNFR2 antisense oligodeoxynucleotides reduced liver metastasis in wild-type mice. Clinically, immunohistochemical analysis of liver metastases from chemotherapy-naïve colon cancer patients confirmed the presence of CD33(+)HLA-DR(-)TNFR2(+) myeloid cells in the periphery of hepatic metastases. Overall, our findings implicate TNFR2 in supporting MDSC-mediated immune suppression and metastasis in the liver, suggesting the use of TNFR2 inhibitors as a strategy to prevent metastatic progression to liver in colon, lung, and various other types of cancer.

AB - Successful colonization by a cancer cell of a distant metastatic site requires immune escape in the new microenvironment. TNF signaling has been implicated broadly in the suppression of immune surveillance that prevents colonization at the metastatic site and therefore must be blocked. In this study, we explored how TNF signaling influences the efficiency of liver metastasis by colon and lung carcinoma in mice that are genetically deficient for the TNF receptor TNFR2. We found a marked reduction in liver metastases that correlated with a greatly reduced accumulation at metastatic sites of CD11b(+)GR-1(+) myeloid cells with enhanced arginase activity, identified as myeloid-derived suppressor cells (MDSC). Reduced infiltration of MDSC coincided with a reduction in the number of CD4(+)FoxP3(+) T regulatory cells in the tumors. Reconstitution of TNFR2-deficient mice with normal bone marrow, or adoptive transfer of TNFR2-expressing MDSC into these mice, was sufficient to restore liver metastasis to levels in wild-type mice. Conversely, treatment with TNFR2 antisense oligodeoxynucleotides reduced liver metastasis in wild-type mice. Clinically, immunohistochemical analysis of liver metastases from chemotherapy-naïve colon cancer patients confirmed the presence of CD33(+)HLA-DR(-)TNFR2(+) myeloid cells in the periphery of hepatic metastases. Overall, our findings implicate TNFR2 in supporting MDSC-mediated immune suppression and metastasis in the liver, suggesting the use of TNFR2 inhibitors as a strategy to prevent metastatic progression to liver in colon, lung, and various other types of cancer.

KW - Adoptive Transfer

KW - Animals

KW - Colonic Neoplasms

KW - Disease Models, Animal

KW - Flow Cytometry

KW - Humans

KW - Immunohistochemistry

KW - Liver Neoplasms

KW - Lung Neoplasms

KW - Lymphocytes, Tumor-Infiltrating

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Microscopy, Confocal

KW - Myeloid Cells

KW - Neoplasm Metastasis

KW - Polymerase Chain Reaction

KW - Receptors, Tumor Necrosis Factor, Type II

KW - Tumor Escape

KW - Tumor Microenvironment

U2 - 10.1158/0008-5472.CAN-14-3173

DO - 10.1158/0008-5472.CAN-14-3173

M3 - Journal article

C2 - 26483205

VL - 75

SP - 5235

EP - 5247

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 24

ER -