Immune-mediated modulation of breast cancer growth and metastasis by the chemokine Mig (CXCL9) in a murine model.
Current immunotherapies are limited by several factors, including the failure to recruit sufficient numbers of immune effector cells to tumors. The chemokine monokine induced by gamma-interferon (Mig; CXCL9) attracts activated T cells and natural killer (NK) cells bearing the chemokine receptor CXCR3. We investigated Mig as an immunotherapeutic agent in a syngeneic murine model of metastatic breast cancer. We transfected the highly malignant murine mammary tumor cell line 66.1 to stably express murine Mig cDNA. Immune-competent mice injected with Mig-expressing tumor cells developed smaller local tumors and fewer lung metastases, and they survived longer than mice injected with vector-control tumor cells. Mig-mediated inhibition of local tumor growth was lost in the absence of host T cells. Mig-transduced tumors had increased numbers of CD4 T cells compared with vector-control tumors, consistent with the T-cell chemoattractant property of Mig, and many tumor-infiltrating host cells expressed CXCR3. NK cells had not been examined previously as a possible effector cell in Mig-based therapies. Our studies now show that NK cells are critical to the mechanism by which Mig limits metastasis. Inhibition of angiogenesis was not implicated as a mechanism of Mig-mediated therapy in this model. These studies support the hypothesis that by manipulating the Mig-CXCR3 gradient, it is possible to direct host immune effector cells to tumors, curtailing both local tumor growth and metastasis. These studies also implicate host NK cells as an additional effector cell critical for Mig-mediated control of metastasis.
Walser
Tonya C
TC
Department of Pathology, University of Maryland School of Medicine, 10 South Pine Street, Baltimore, MD 21201, USA.
Ma
Xinrong
X
Kundu
Namita
N
Dorsey
Russell
R
Goloubeva
Olga
O
Fulton
Amy M
AM
D000230:Adenocarcinoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009389:Neovascularization, Pathologic
D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse