Biology subjects

Apetoh, L.

Publications and source records attributed to Apetoh, L..

2 recordsLinked to original sources

bioRxiv2026

CASM potentiates STING-driven NFκB signaling in immune cells

Stimulator of Interferon Gene (STING), a key player of antimicrobial immune responses, has emerged as a promising target to mitigate inflammation and cancer. Following STING activation, proinflammatory molecules and type I Interferons (IFN) are released thus favoring the establishment of effective immune responses and adaptive immunity. Autophagy has been proposed to negatively regulate STING signaling. While STING activation drives microtubule-associated proteins 1A/1B light chain 3B (hereafter referred to as LC3) lipidation, the underlying mechanisms and functional consequences remain however incompletely defined. Especially, the consequences of STING-associated Conjugation of autophagy related (ATG) 8 to Single Membranes (CASM) in the control of immune responses remain elusive. Using innate and adaptive cells specifically inactivated for autophagy or CASM, we found that STING agonists primarily trigger CASM over autophagy. While STING-associated autophagy exerts negative feedback on the STING pathway and downstream type I IFN and pro-inflammatory responses, with different underlying molecular mechanisms between immune cells, STING-driven CASM potentiates NF{kappa}B-associated TNF production. These results overall uncover a new function of CASM and underscore the relevance of both CASM and autophagy in shaping STING signaling

cell biology↗

bioRxiv2023

Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression

Immune checkpoint blockade (ICB) has revolutionized cancer therapy but has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. We demonstrate that NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the NLRP3 inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Loss of NR0B2 increased mammary tumor growth and metastasis. Small molecule agonists, including one developed here, reduced Treg expansion, reduced metastatic growth and improved the efficacy of ICB. This work identifies NR0B2 as a target to re-educate myeloid immune cells providing proof-of-principle that this cholesterol-homeostasis axis may have utility in enhancing ICB. Brief SummaryImmune therapy has been disappointing for breast cancer. NR0B2 within myeloid immune cells reduces the expansion of Tregs, a highly immune suppressive subtype historically challenging to target. NR0B2 within myeloid immune cells represses the inflammasome, leading to reduced Treg expansion and subsequent tumor growth/metastasis. Activation of NR0B2 with small molecule agonists, including one developed herein, attenuates tumor growth and metastasis in murine models of mammary cancer.

cancer biology↗