CXCR3/CXCR3 Ligand Biological Axis Impairs RENCA Tumor Growth by a Mechanism of Immunoangiostasis

Abstract

RATIONALE Metastatic renal cell carcinoma (RCC) responds poorly to chemo‐ or radiation therapy but responds to systemic immunotherapy, albeit with low response rate. We hypothesized that the CXCR3/CXCR3 ligand biological axis could be optimized to attenuate RCC by first priming with systemic IL‐2 followed by enhancing the intratumor CXCR3 ligand levels to establish optimal CXCR3 ligand chemotactic gradient. METHODS We examined the CXCR3 ligand gradient in a murine RCC (RENCA) model and studied the anti‐tumor effect of various strategies in CXCR3−/− or CXCR3+/+ mice bearing RENCA. RESULTS Systemic IL‐2 induced the expression of CXCR3 on circulating mononuclear cells but impaired the CXCR3 ligand chemotactic gradient from plasma to tumor. IL‐2 failed to inhibit tumor growth and angiogenesis in CXCR3−/− mice. Combined systemic IL‐2 with an intratumor CXCR3 ligand led to significantly greater reduction in tumor growth and angiogenesis, increased tumor necrosis, and increased infiltration of CXCR3+ mononuclear cells, as compared to either strategy alone. These enhanced effects were associated with increased tumor‐specific immune response. CONCLUSIONS These data suggest that combined systemic IL‐2 and intratumor CXCR3 ligand is more efficacious than either strategy alone for reducing tumor‐associated angiogenesis and augmenting tumor‐associated immunity‐the concept of immunoangiostasis. FUNDED BY: NIH Grants CA87879, P50CA90388, HL66027, and P50HL67665.

Chemokines as mediators of angiogenesis

“…These findings are similar to the previously reported study of IL-12-mediated regression of renal cell carcinoma in a murine model, where the anti-tumour effect of IL-12 was lost when CXCR3 ligands were depleted (129). More recently, the effectiveness of systemic IL-2 therapy in the mouse model of renal cell carcinoma was shown to be CXCR3-dependent, and resulted in up-regulation of CXCR3 on peripheral blood mononuclear cells but, surprisingly, down-regulation of CXCR3 ligands in the tumour (125). The effectiveness of this therapy was substantially enhanced when it was combined with over-expression of the CXCR3 ligand, CXCL9, in the tumour (125).…”

“…More recently, the effectiveness of systemic IL-2 therapy in the mouse model of renal cell carcinoma was shown to be CXCR3-dependent, and resulted in up-regulation of CXCR3 on peripheral blood mononuclear cells but, surprisingly, down-regulation of CXCR3 ligands in the tumour (125). The effectiveness of this therapy was substantially enhanced when it was combined with over-expression of the CXCR3 ligand, CXCL9, in the tumour (125). Taken collectively, these findings support the notion that CXCR3 and its ligands contribute to anti-tumour defenses by two distinct and additive mechanisms, namely inhibition of angiogenesis and mediating direct anti-tumour immunity.…”

“…The observation that CXCR3 and its ligands both inhibit angiogenesis and mediate Th1-type cell mediated immunity via recruitment of CXCR3-expressing T cells (120)(121)(122)(123)(124) has led to the concept of "immunoangiostasis" in cancer (125,126). As an example of this, intratumoural injection of a recombinant CC chemokine, CCL21, in tumours induced regression via spatial generation of intratumour IFN-γ, consequent CXCR3 ligands, and influx of CXCR3-expressing CD4, CD8, natural killer, and dendritic cells into both the tumour and the draining lymph nodes, in addition to a reduction in angiogenesis (127,128).…”

Chemokines in cancer related inflammation

“…In gastric and colorectal carcinoma [49,50] significant levels of CXCL9 and CXCL10 are produced by stromal cells, and are correlated with CXCR3-positive TIL. Murine tumors engineered with CXCL9 or CXCL10 [51,52], and intra-tumor injection of CXCL9 [48] further demonstrated the ability of these chemokines to recruit T as well as NK cells and to elicit antitumoral responses.…”

“…In diverse human tumors, especially in colorectal cancer, an abundance of TIL is a strong prognostic factor and active research is focusing on the chemokines responsible for their recruitment [46,47]. TIL have been reported to express the CXCR3 receptor; the corresponding ligands CXCL9 and CXCL10 can elicit anti-tumoral responses which correlated with increased infiltration of CD4 and CD8 lymphocytes [48]. In gastric and colorectal carcinoma [49,50] significant levels of CXCL9 and CXCL10 are produced by stromal cells, and are correlated with CXCR3-positive TIL.…”