Complement C1q binding protein regulates T cells' mitochondrial fitness to affect their survival, proliferation, and anti-tumor immune function.

Abstract

T cells survival, proliferation, and anti–tumor response are closely linked to their mitochondrial health. Complement C1q binding protein (C1QBP) promotes mitochondrial fitness through regulation of mitochondrial metabolism and morphology. However, whether C1QBP regulates T cell survival, proliferation, and anti–tumor immune function remains unclear. Our data demonstrated that C1QBP knockdown induced the accumulation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential to impair T cell mitochondrial fitness. At the same time, C1QBP insufficiency reduced the recruitment of the anti–apoptotic proteins, including Bcl‐2 and Bcl‐XL, and repressed caspase‐3 activation and poly (ADP‐ribose) polymerase cleavage, which consequently accelerated the T cell apoptotic process. In contrast, C1QBP knockdown rendered T cells with relatively weaker proliferation due to the inhibition of AKT/mTOR signaling pathway. To investigate the exact role of C1QBP in anti–tumor response, C1QBP+/− and C1QBP+/+ mice were given a subcutaneous injection of murine MC38 cells. We found that C1QBP deficiency attenuated T cell tumor infiltration and aggravated tumor‐infiltrating T lymphocytes (TIL) exhaustion. Moreover, we further clarified the potential function of C1QBP in chimeric antigen receptor (CAR) T cell immunotherapy. Our data showed that C1QBP+/− CAR T cells exhibited relatively weaker anti–tumor response than the corresponding C1QBP+/+ CAR T cells. Given that C1QBP knockdown impairs T cells’ anti–apoptotic capacity, proliferation as well as anti–tumor immune function, development of the strategy for potentiation of T cells’ mitochondrial fitness through C1QBP could potentially optimize the efficacy of the related immunotherapy.