scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity

Abstract

ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein with an activity in inhibition of F 1 F o -ATP synthase. ATPIF1 activity remains unknown in the control of immune activity of T cells. In this study, we identified ATPIF1 activity in the induction of CD8 + T cell function in tumor models through genetic approaches. ATPIF1 gene inactivation impaired the immune activities of CD8 + T cells leading to quick tumor growth (B16 melanoma and Lewis lung cancer) in ATPIF1-KO mice. The KO T cells exhibited a reduced activity in proliferation and IFN-γ secretion with metabolic reprogramming of increased glycolysis and decreased oxidative phosphorylation (OXPHOS) after activation. T cell exhaustion was increased in the tumor infiltrating leukocytes (TILs) of KO mice as revealed by the single-cell RNA sequencing (scRNA-seq) and confirmed by flow cytometry. In contrast, ATPIF1 overexpression in T cells increased expression of IFN-γ and Granzyme B, subset of central memory T cells in CAR-T cells, and survival rate of NALM-6 tumor-bearing mice. These data demonstrate that ATPIF1 deficiency led to tumor immune deficiency through induction of T cell exhaustion. ATPIF1 overexpression enhanced the T cell tumor immunity. Therefore, ATPIF1 is a potential molecular target in the modulation of antitumor immunity of CD8 + T cells in cancer immunotherapy. Induction of ATPIF1 activity may promote CAR-T activity in cancer therapy.

Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity

“… 144 , 192 ATPIF1 knockdown in allogeneic CD19 CAR‐Ts increases the glycolytic activity to compensate for mitochondrial defects while decreasing the ability of these cells to generate ATP via other energy substrates, such as fatty acids or amino acids, which inhibits CD8+ Tm formation and virulence factor production and accelerates CD8+ Teff exhaustion. 159 In summary, both the glycolysis inhibitor 2‐DG and selective PI3K inhibitors may contribute to an increased Tcm/Tem ratio and limit CAR‐T glycolytic activity to maintain persistent stemness. 160 , 161 , 193 Notably, activation of the TGF‐β/Smad signalling pathway in the hypoxic TME tends to reduce T‐cell glycolytic competitiveness 194 ; therefore, the knockdown of TGF‐βR2 in CAR‐Ts inhibits TGF‐β signalling to facilitate CAR‐T survival in vivo and increase the tumour elimination efficacy.…”

“…The electron transport chain(ETC) complex V inhibitory protein adenosine triphosphate inhibitory factor 1 (ATPIF1) maintains the mitochondrial structure and the functional stability of the electron transport chain 144,192 . ATPIF1 knockdown in allogeneic CD19 CAR‐Ts increases the glycolytic activity to compensate for mitochondrial defects while decreasing the ability of these cells to generate ATP via other energy substrates, such as fatty acids or amino acids, which inhibits CD8+ Tm formation and virulence factor production and accelerates CD8+ Teff exhaustion 159 . In summary, both the glycolysis inhibitor 2‐DG and selective PI3K inhibitors may contribute to an increased Tcm/Tem ratio and limit CAR‐T glycolytic activity to maintain persistent stemness 160,161,193 .…”

Cell metabolism-based optimization strategy of CAR-T cell function in cancer therapy

“…ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein that inhibits F 1 F o -ATP synthase ( 174 ), which lead to decreased glycolysis and increased oxidative phosphorylation (OXPHOS). ATPIF1 overexpression in T cells can increase the expression of IFN-γ and granzyme B, the subset of central memory T cells in CAR-T cells, and the survival rate of NALM-6 tumor-bearing mice ( 175 ).…”