Abstract 113: c-Kit-dependent tissue resident macrophage progenitors drive cancer progression

Abstract

Abstract Macrophages play a key role in promoting tumor growth and resistance to therapy. Here we show that Tissue Resident Macrophages (TRM) as well as Bone Marrow-Derived Macrophages (BMDM) play critical but unique roles in promoting tumor growth. TRM were recently shown to originate in the yolk sac or fetal liver during embryogenesis; these cells self-maintain in post-natal tissues independent of hematopoietic stem cells. We found that BMDM are CD11b+Gr1+F4/80loCX3CR1loCCR2+and are recruited to tumors in a CCR2-dependent manner. In contrast, CD11b+Gr1-F4/80hiCX3CR1hiCCR2- TRMs accumulate in tumors independently of the trafficking receptor CCR2. Gene expression and functional studies indicate that tumor-derived TRM are highly proliferative, immune suppressive and distinct from BMDM. We show that TRM develop from c-Kit/c-KitL - dependent TRM progenitors that are abundant in tumors but not in normal tissues; purified progenitors form macrophages and potently stimulate tumor growth when adoptively transferred into mice. Tumor cells induce the expansion of TRM progenitors by secreting Stem Cell Factor (SCF/c-KitL). Notably, in vitro and in vivo proliferation of TRM progenitors and tumor growth are significantly inhibited by SCF and c-Kit inhibitors, including a novel, allosteric dual inhibitor of cKit and CDK8/19 that dramatically suppresses tumor growth by targeting both TRM and tumor cells. As cKit inhibitors synergize with other immune therapy regimens to suppress tumor growth, our studies identify cKit as a valuable target for immune therapy of solid tumors. Citation Format: Paulina Pathria, Hideyuki Takahashi, Megan Kaneda, Minya Pu, Karen Messer, Ryan M. Shepard, Tiani L. Louis, Ann Shih, Mark Bertagnolli, Wolfgang Wrasidlo, David A. Cheresh, Judith A. Varner. c-Kit-dependent tissue resident macrophage progenitors drive cancer progression [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 113.