Abstract
AbstractHER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor associated macrophages (TAMs). While TAMs consist of the immune-stimulatory M1-type and immune-suppressive M2-type, M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1 vs. M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2- TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- vs M2-TAMs is attributed to different availability of BH4(NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4precursor, elevates the expression of M1- TAM markers within HER2+ tumors. Here, we show that SEP restores BH4levels in M2-TAMs, which then redirects arginine metabolism to NO synthesis and converts M2-TAMs to M1-TAMs. The reprogrammed TAMs exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in metabolic shift of HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.
Publisher
Cold Spring Harbor Laboratory
Reference76 articles.
1. Induction of Vascular GTP-Cyclohydrolase I and Endogenous Tetrahydrobiopterin Synthesis Protect Against Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis
2. Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches;Breast Cancer (Dove Med Press),2019
3. Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation
4. Barker, R.N. , Erwig Lp Fau - Hill, K.S.K. , Hill Ks Fau - Devine, A. , Devine A Fau - Pearce, W.P. , Pearce Wp Fau - Rees, A.J. and Rees, A.J. (2002) Antigen presentation by macrophages is enhanced by the uptake of necrotic but not apoptotic cells.
5. Classification of M1/M2- polarized human macrophages by label-free hyperspectral reflectance confocal microscopy and multivariate analysis;Scientific Reports,2017