TNF Receptor-2 Facilitates an Immunosuppressive Microenvironment in the Liver to Promote the Colonization and Growth of Hepatic Metastases.
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.
Department of Medicine, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada.
Boram
B
Ham
Department of Surgery, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada.
Ni
N
Wang
Department of Surgery, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada.
Zarina
Z
D'Costa
Department of Surgery, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada.
Maria Celia
MC
Fernandez
Department of Surgery, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada.
France
F
Bourdeau
Université de Bordeaux, Talence, France. INSERM, LAMC, UMR 1029, Talence, France.
Patrick
P
Auguste
The Finsen Laboratory, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
Martin
M
Illemann
The Finsen Laboratory, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Rikke Loevendahl
RL
Eefsen
The Finsen Laboratory, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
Gunilla
G
Høyer-Hansen
Department of Pathology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
Ben
B
Vainer
Université Paris-Diderot, Paris, France.
Maximilien
M
Evrard
Department of Pathology, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada.
Zu-Hua
ZH
Gao
Department of Medicine, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada. Department of Surgery, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada. pnina.brodt@mcgill.ca.
Pnina
P
Brodt
D019264:Adoptive Transfer; D000818:Animals; D003110:Colonic Neoplasms / Q000556:secondary; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000276:immunology* / Q000556:secondary*; D008175:Lung Neoplasms / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000276:immunology; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
D047889:Receptors, Tumor Necrosis Factor, Type II