Abstract SY19-01: TGFβ and immune evasion in metastatic cancer

Abstract

Abstract TGF-β and Immune Evasion in Metastatic Cancer Transforming growthfactor-β (TGF-β) is a major regulator of development,immune homeostasis, tissue regeneration, and cancer. TGF-β signaling suppresses tumor initiation but promotestumor progression through mechanisms that are increasingly understood. TGF-β inhibitsthe expansion and function of many components of the immune system and itspresence in the tumor microenvironment limits the effectiveness of current immunotherapies. To betterdefine the potential benefit of targeting TGF-β in cancer, we investigated therole of TGF-β in metastasis. Metastasis, the main cause of deathfrom cancer, is driven by stem-like disseminated cancer cells (“metastasisinitiating cells”, MICs) capable of reversible quiescence, immune evasion, organ-specificoutgrowth, and drug resistance. We developed models oflung adenocarcinoma (LUAD) metastatic dormancy and outbreak by isolating MICs thatrecapitulate the developmental and regenerative phenotypes of carcinoma cellsin human metastases. We find that TGF-β in thetumor microenvironment has different tumorigenic effects on early-stageprogenitor MICs and their progenies. In SOX2-rich early progenitor MICs, TGF-βinduces dormancy by imposing a growth-inhibited epithelial to mesenchymaltransition (EMT). Pharmacologic inhibition of TGF-β in this context causes MICsto exit from this immune evasive dormancy and become exposed to immune attack. Incontrast, SOX9-rich MIC progeny cells respond to TGF-β with an EMT that iscoupled to expression of fibrogenic cytokines. Deletion of TGF-β receptor orits fibrogenic target genes in the carcinoma cells prevents intratumoralfibrosis and inhibits metastatic outgrowth. These insights suggest that targetingTGF-β in metastatic cancer can improve treatment outcomes by forcing MICs outof immune evasive quiescence and suppressing intra-tumoral fibrosis, inaddition to relieving innate and adaptive immunity from TGF-β mediated inhibition. Citation Format: Joan Massagué. TGFβ and immune evasion in metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY19-01.