Abstract C227: Blockade of tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor overcomes tumor recurrence after radiation therapy.

Abstract

Radiotherapy is one of the major frontline treatments for prostate cancer (PCa). However, a large proportion of patients suffer from tumor recurrence after radiotherapy. Tumor-infiltrating myeloid cells (TIMs), including CD11b+F4/80+ tumor-associated macrophages (TAM) and CD11b+Gr-1+ myeloid-derived suppressive cells (MDSCs), play critical roles in promoting tumoral angiogenesis, tissue remodeling and immunosuppression. Recently several reports suggested that TIMs might play a critical role in mediating tumor regrowth after radiation therapy. Here, we showed that there is enhanced recruitment of both TAMs and MDSCs after 5 days of 3 Gy radiation treatment in subcutaneously implanted RM-1 syngeneic PCa model. Infiltration of two MDSC subsets, CD11b+Gr-1loLy6Chi mononuclear-MDSC (MO-MDSC) and CD11b+Gr-1hiLy6Clo polymorphnuclear-MDSC (PMN-MDSC), are both increased. Although treatment is localized to the tumor site, the effects of radiation are systematic. Dramatic increases of MDSCs and TAMs were also observed in the spleen, lymph nodes and peripheral blood. To better understand the mechanism of enhanced recruitment of myeloid cells to tumors, we performed RT-PCR analysis on tumor tissues for commonly known factors that mediate the recruitment of myeloid cells. Indeed, we found that macrophage colony stimulating factor 1 (M-CSF-1 or CSF-1) increases by 2 fold in irradiated tumors compared to non-irradiated tumors. In vitro migration assays using conditioned medium from irradiated tumor cells increases migration of RAW246.7 macrophages by 4 fold, and this increase is completely blocked by the very selective CSF1R inhibitor, GW2580. Immunohistochemical analysis confirmed the induction of TAMs and MDSC recruitment to tumors, and the effectiveness of GW2580 in blocking their infiltration. Most importantly, combination therapy using GW2580 with radiation synergistically suppressed tumor growth and recurrence. This data highlights the importance of CSF1/CSF1R signaling in the recruitment of TIMs post-radiation treatment and their significant role in promoting tumor re-growth. Moreover, our data could potentially provide a more effective and durable treatment strategy for PCa patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C227.

Enhanced Cancer Radiotherapy through Immunosuppressive Stromal Cell Destruction in Tumors

“…Success was reported in experiments blocking the recruitment of CD11b+ myeloid cells to the irradiated tumor and directly depleting myeloid cells (10, 11, 47, 49, 50). However, most of these approaches result in global myeloid cell depletion and systemic blockage of myeloid cell migration, which raises concerns of interrupting the homeostatic functions of these cells in various organs resulting in toxicities (51).…”