title: CXCR3/CXCR3 ligand biological axis impairs RENCA tumor growth by a mechanism of immunoangiostasis.
abstract: Metastatic renal cell carcinoma (RCC) responds poorly to chemo- or radiation therapy but appears to respond to systemic immunotherapy (i.e., IL-2 and/or IFN-alpha), albeit with only 5-10% durable response. The CXCR3/CXCR3 ligand biological axis plays an important role in mediating type 1 cytokine-dependent cell-mediated immunity, which could be beneficial for attenuating RCC if optimized. We found that systemic IL-2 induced the expression of CXCR3 on circulating mononuclear cells but impaired the CXCR3 ligand chemotactic gradient from plasma to tumor by increasing circulating CXCR3 ligand levels in a murine model of RCC. Moreover, the antitumor effect of systemic IL-2 was CXCR3-dependent, as IL-2 failed to inhibit tumor growth and angiogenesis in CXCR3-/- mice. We hypothesized that the immunotherapeutic effect of the CXCR3/CXCR3 ligand biological axis could be optimized by first priming with systemic IL-2 to induce CXCR3 expression on circulating mononuclear cells followed by enhancing the intratumor CXCR3 ligand levels to establish optimal CXCR3-dependent chemotactic gradient. We found that combined systemic IL-2 with an intratumor CXCR3 ligand (CXCL9) lead to significantly greater reduction in tumor growth and angiogenesis, increased tumor necrosis, and increased intratumor infiltration of CXCR3+ mononuclear cells, as compared with either IL-2 or CXCL9 alone. The enhanced antitumor effect of the combined strategy was associated with a more optimized CXCR3-dependent chemotactic gradient and increased tumor-specific immune response. These data suggest that the combined strategy of systemic IL-2 with intratumor CXCR3 ligand is more efficacious than either strategy alone for reducing tumor-associated angiogenesis and augmenting tumor-associated immunity, the concept of immunoangiostasis.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Judong
authors.initials: J
authors.lastname: Pan
authors.forename: Marie D
authors.initials: MD
authors.lastname: Burdick
authors.forename: John A
authors.initials: JA
authors.lastname: Belperio
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Xue
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D002465:Cell Movement / Q000276:immunology; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000378:metabolism* / Q000627:therapeutic use; D006131:Growth Inhibitors / Q000378:metabolism / Q000502:physiology / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D006131:Growth Inhibitors; D007376:Interleukin-2; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine