Mitochondrial C1QBP is essential for T cell antitumor function by maintaining mitochondrial plasticity and metabolic fitness

Abstract

The metabolic stress present in tumors microenvironment (TME) attenuates T cells anti-tumor capacity, whereas the immune function of T cells is intrinsically controlled by their mitochondrial plasticity including mitochondrial dynamics, metabolism and biogenesis. Previous studies have reported that the complement C1q binding protein (C1QBP), a mitochondrial protein, is responsible for maintenance of the mitochondrial integrity and tness in dendritic cells and tumor cells. However, its role in T cells, especially in T cells mediated anti-tumor immunity, remains unclear. Here we show that C1QBP is required to maintain T cell anti-tumor immunity by regulating mitochondrial biogenesis, dynamics and metabolic tness even when only one allele of C1qbp is deleted, without affecting T cells development and homeostasis. Further analysis of C1QBP in the chimeric antigen receptor (CAR) T cell therapy against B16 melanoma model con rmed the cell intrinsic role of C1QBP in regulating T cells antitumor function.Mechanistically, we found C1QBP regulated mitochondrial plasticity and metabolic tness through mitochondrial biogenesis via the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) signaling pathway, as well as mitochondrial morphology via the phosphorylation of mitochondrial dynamics protein dynamin-related protein 1 (Drp1). In summary, our study provides a novel mitochondrial target to reprogram the immune metabolism of T cells and improve their immunotherapeutic potential against tumors.

Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication

“…2 F). Among those 84 genes, several genes have been reported to be related to immune activity, such as C1QBP [ 57 ], TUFM [ 58 ], LDHA [ 59 ], LDHB [ 60 ] and ACAT1 [ 61 ].…”

PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP

“…Considering that C1QBP is a vital protein for maintaining mitochondrial metabolism (Tian et al, 2023), we further investigated the function underlying the malignant progression of OSCC through the interaction between PA28γ and C1QBP in vitro and in vivo. PA28γ and C1QBP colocalized in the mitochondria, and the stabilization of C1QBP by PA28γ enhanced mitochondrial morphology and OXPHOS.…”

Targeting metabolism to improve CAR-T cells therapeutic efficacy

“…[117] Complement C1q binding protein (C1QBP), another mitochondrial protein, was also con rmed to play an indispensable role in the antitumor activity of CAR-T cells by maintaining mitochondrial biogenesis and morphology through AMPK-PPAR1 and the mitochondrial dynamics protein dynamin-related protein 1 signaling. [118] β2-adrenergic receptor (β2-AR) is another potential targetable checkpoint in boosting the ef ciency of CAR-T cell therapy via modulating metabolic reprogramming, [119] especially in the mitochondrial metabolism. The inhibition of β2-AR signaling increases mitochondrial biogenesis, respiration capacity, and membrane potential.…”