Abstract B003: Reprogramming of fibrotic macrophages to control DCIS progression

Abstract

Abstract Women with aggressive DCIS are at high risk of progression to invasive breast cancer. Invasive disease is accompanied by extensive collagen remodeling and crosslinking that contributes to tissue fibrosis and stiffness. Fibrotic breast tumors are associated with an immune desert or immune excluded tumor microenvironment (TME) that functions to promote tumor progression. In particular, tumor-associated macrophages (TAMs) promote tumor invasion and metastasis and, drive immune suppression allowing tumors to evade intrinsic anti-tumor immune responses. Here, we show that collagen remodeling and crosslinking and tissue stiffness associate with DCIS progression and recurrence to invasion in patient tissues. The fibrotic and stiff TME promotes DCIS progression in a mouse model in part by inducing a suppressive TAM phenotype characterized by epigenetic and metabolic reprogramming that accompanies an impaired pro-inflammatory gene signature, as seen in tolerant macrophages. TAMs can be polarized by toll-like receptor (TLR) agonists to eliminate tumor cells by producing pro-inflammatory cytokines or by stimulating cytotoxic T cells, though these are poor cancer therapies alone. Thus, we hypothesized to improve the TLR agonists anti-tumor effects, we can reprogram the metabolic pathways associated with macrophage tolerance, and these together may control DCIS progression in fibrotic and stiff TMEs. We show that fibrotic TAMs can be reprogrammed with monophosphoryl lipid A (MPLA) and coenzyme A (CoA) to kill tumor cells. MPLA + CoA injected into the mammary fat pad reduces high risk features of DCIS in this breast cancer mouse model. We show that CoA supplementation alters macrophage metabolism by supporting acetyl-CoA production needed for histone acetylation and pro-inflammatory gene transcription. MPLA + CoA reprograms CD206+ TAMs to inducible NO synthase (iNOS)+ macrophages and activates cytotoxic T cells through macrophage-secreted cytokines. This treatment approach for engaging an anti-tumor immune response represents an alternative treatment to that of current invasive surgery options for women with high-risk DCIS. Citation Format: Mary-Kate Hayward, Greg A. Timblin, Jason J. Northey, Connor Stashko, Alastair J. Ironside, E. Shelley Hwang, Valerie M. Weaver. Reprogramming of fibrotic macrophages to control DCIS progression [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B003.