RT Journal Article
SR Electronic
T1 Reprogramming of breast tumor–associated macrophages with modulation of arginine metabolism
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302339
DO 10.26508/lsa.202302339
VO 7
IS 11
A1 Fernando, Veani
A1 Zheng, Xunzhen
A1 Sharma, Vandana
A1 Sweef, Osama
A1 Choi, Eun-Seok
A1 Furuta, Saori
YR 2024
UL http://www.life-science-alliance.org/content/7/11/e202302339.abstract
AB HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus 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- versus 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 BH4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages 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 the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.