Abstract IA19: Multiplexing TGFβ in the tumor microenvironment

Abstract

Abstract The dynamics of TGFβ biology is context dependent. TGFβ is controlled at many levels with a major mechanism in its production as a latent complex from which TGFβ is released extracellularly. TGFβ production and activity is greatly increased in many cancer cells. Tumor microenvironment can also be a significant TGFβ source, particularly bone marrow derived cells (BMDC). TGFβ regulates malignant behaviors and cell phenotype of tumor microenvironment constituents locally and the hematopoietic and immune systems at a distance. We investigated the contribution of TGFβ to the effects of radiotherapy in breast, brain and lung cancer murine models. Our studies show that radiation induces rapid TGFβ activation that can persist for days. Radiation induced TGFβ promotes rapid and effective DNA damage response, mediates tumor microenvironment composition, regulates BMDC recruitment and phenotype, and augments immune evasion. Inhibition of TGFβ during radiotherapy provides significant therapeutic benefit by molecular and microenvironmental mechanisms. TGFβ inhibition during radiotherapy impedes DNA damage recognition, which promotes tumor cell death and thus, tumor growth control. Continued TGFβ inhibition prevents vascular remodeling necessary for tumor regrowth, and blocks BMDC recruitment, which limits an exogenous TGFβ source. Multiplexing these actions with those on tumor immunity suggest potent therapeutic potential of TGFβ inhibition during radiotherapy to eliminate tumor cells and eradicate tumor promoting microenvironments. Citation Format: Mary Helen Barcellos-Hoff. Multiplexing TGFβ in the tumor microenvironment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA19. doi:10.1158/1538-7445.CHTME14-IA19