Abstract 6010: Tumor mhicroenvironment effects on hematopoietic stem cell induced tumor growth following radiation therapy

Abstract

Abstract The tumor microenvironment (TME), comprised of tumor tissue, stromal cells, extracellular matrix (ECM), bone marrow (BM)-derived immune cells, and various signaling molecules, rarely remains static. These components continuously respond to internal and external stimuli to promote tumor progression as well as regrowth after therapy. Recently, we reported that functional BM-derived hematopoietic stem and progenitor cells (HSPCs) take up residence within growing lung tumors. Interestingly, when tumors were exposed to radiation therapy (RT) there was a significant increase in HSPC numbers within tumors (p<0.003). These HSPCs seemed to positively affect tumor regrowth as their numbers directly correlated with regrowth rates (R2=.4875). To determine the role of HSPCs in tumor growth we proposed a mechanism wherein tumor-associated HSPCs are maintained within tumors but following exposure to RT can differentiate into tumor-supportive macrophage populations, thus aiding in tumor regrowth. To test this hypothesis, Lewis Lung Carcinoma tumors were subcutaneously generated in mice and exposed to either RT or no radiation treatment (NRT). Analysis using RT-PCR and immunohistochemistry demonstrated that RT produces TME conditions that favor the differentiation of HSPCs into tumor-supportive M2-macrophages through the increased production of colony stimulating factor 1 (CSF-1) (p<0.005). In addition, we show that inhibition of CSF-1R phosphorylation using a pharmacologic inhibitor (GW2580) had no effect on HSPCs numbers but resulted in significantly decreased M2 macrophage numbers resulting in decreased tumor growth and regrowth (p<0.005). Furthermore, we found that the interaction of HSPC-bound integrin α6 with Laminin 5-1-1 is associated with HSPC maintenance within tumors. Interestingly, Laminin 5-1-1 levels were decreased in RT treated tumors compared to NRT controls (p<0.005) further indicating that the RT-derived microenvironments supported HSPC differentiation into M2 macrophages. Overall, these studies define a new understanding of tumor biology in which tumor-associated HSPCs are an essential component of tumor progression and survival and identify new treatment strategies to overcome these effects and achieve more optimal clinical outcomes. Citation Format: Tyler M. Parsons, Katie Buelow, Alaa Hanna, Sandra Galoforo, George Wilson, Gerard Madlambayan. Tumor mhicroenvironment effects on hematopoietic stem cell induced tumor growth following radiation therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6010.