| First Author | Fernando V | Year | 2024 |
| Journal | Life Sci Alliance | Volume | 7 |
| Issue | 11 | PubMed ID | 39191486 |
| Mgi Jnum | J:353832 | Mgi Id | MGI:7713737 |
| Doi | 10.26508/lsa.202302339 | Citation | Fernando V, et al. (2024) Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism. Life Sci Alliance 7(11) |
| abstractText | 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 BH(4) (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH(4) precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH(4) 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. |
