Abstract LB-316: Suppression of tumor angiogenesis and metastasis by targeting a novel p38-driven tumor-stromal crosstalk

Abstract

Abstract Triple-negative breast cancers (TNBCs, ER/PR/HER2-negative) pose significant clinical challenges largely due to a lack of targeted therapy. Our prior work revealed a novel tumor-stromal crosstalk that increases p38 kinase signaling in the breast tumor microenvironment (TME). Here, we examined the effects of systemic blockade of p38 signaling in the relevant TNBC models. Blockade of p38 with a selective p38 inhibitor Ralimetinib reduced tumor growth and metastasis to the lungs and liver. Histology revealed that p38 blockade greatly reduced tumor angiogenesis. Within the TME, we found a massive infiltration of myeloid cells i.e. polymorphonuclear (PMN) myeloid-derived suppressor-like cells (MDSC-like) to the lungs and liver of tumor-bearing (TB) mice. Further, TB-mice showed a significant rise in the numbers of granulocytes and monocytes in the circulation, and the accumulation of CD163+ macrophages in the TME. Blockade of p38 greatly reduced these responses. In contrast, p38 blockade increased abundance of cytotoxic CD8+ T-cells in the TME. Addressing the mechanism, we found that inactivation of p38 in tumor cells was sufficient to reduce the influx of macrophages to the tumor, suggesting a tumor-driven mechanism of mobilization or expansion of myeloid cell populations. Further, depletion of PMN-MDSC-like cells and neutrophils using anti-Ly6G antibody reduced metastases to the lungs and liver. Assessing the prognostic value of our results, we found an inverse correlation of CD163 levels with metastasis-free survival in patients with breast cancer. Together, these results demonstrate that p38 kinase promotes breast cancer growth and colonization to distant organs by regulating mobilization of pro-tumor myeloid cells. This p38-driven mechanism highlights a novel target for treatment of patients with TNBC or advanced disease. Citation Format: Andrei V. Bakin, Justin Zonneville, Rebecca Walden, Sydney Grant, Sean Colligan, Alexandra Miller, Alexander M. Truskinovsky, Scott Abrams. Suppression of tumor angiogenesis and metastasis by targeting a novel p38-driven tumor-stromal crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-316.