CD38-NAD+-Sirt1 axis in T cell immunotherapy

as a powerful therapeutic intervention against various malignancies. In past few years remarkable clinical successes have been achieved in treating cancer patient’s by bolstering the anti-tumor T cell response either by adoptively transferring tumor epitope specific TCR or CAR engineered T cells or by antibody mediated blockade of co-inhibitory immune checkpoints (PD1, CTLA4, Lag3, Tim3) on tumor reactive T cells [1]. While these therapies benefit a fraction of patients with malignancy, majority of them either do not respond to these therapies or experience tumor relapse after initial response due to T cell dysfunction in the tumor microenvironment. Therefore, understanding the T cell intrinsic factors that would instill tumor reactive T cells with a stable functional state at the tumor site is warranted. Recent studies have demonstrated that the T cell dysfunctionality in tumors is a dynamic process, which involves remodeling of the epigenetic pathways that lead to a compact chromatin state and reduced transcription of genes associated with effector function [2]. Additionally, the cellular energetic pathway is also a key feature of the unresponsive state of anti-tumor T cells. Most intriguingly, mitochondrial quality and integrity that ensures efficient oxidative phosphorylation (OXPHOS) appears to be decisive in regulating the durability and ability of the anti-tumor T cells to respond to immunotherapeutic regimen [3]. However, what connects these seemingly unrelated cellular events of attaining a distinct chromatin and metabolic state that reinforces the stable dysfunction in anti-tumor T cells. Recently, using tumor epitope reactive T cells that were ex vivo programmed to secrete both IFN-γ and IL17 at the time of adoptive transfer, we identified that CD38NAD+-Sirt1 axis acts as a key determinant of the therapeutic efficacy of anti-tumor T cells [4] (Figure 1). CD38 is an ectonucleotidase with NADase activity highly expressed on tumor infiltrating lymphocytes (TILs), and its expression increases as tumor progresses. T cells with genetic ablation of CD38 not only exhibited complete remission of tumor growth but also improved the durability of the response. Most, notable feature observed in T cells with CD38 deficiency was its preferential reliance on glutaminolysis to empower OXPHOS. We believe that thid metabolic reprogramming is critical to sustain the effector Editorial