Mitochondrial reprogramming to restore age-driven dysfunction in T cell and boost CAR-T cell therapy
Nicola Vannini
PhDUniversite de Lausanne
Project Term: July 1, 2024 - June 30, 2027
In the Cancer Immunology field, the “aging” variable has not been investigated profoundly yet, even though aging is the first factor associated to cancer. This represents a major limitation on the significance of the experimental results and their translation to the clinic. We believe that with our proposal we can shade light on important biological processes which drive immunotherapy failure. We have shown that T cell function is dependent not only on the differentiation state but also on their biological age. Thus, taking in consideration aging and the age-driven metabolic defects in T cells will help to better understand their biology and develop better strategies to boost immunotherapy.
Over the past years my laboratory has characterized the metabolic profiles of hematopoietic stem and progenitor compartments and identified mitochondria as master regulators of hematopoietic stem cell (HSC) and T cell function and fate.
We demonstrated that mitochondrial activity is a functional predictor of HSC capacity to reconstitute a functional blood and immune system and establish a link between mitophagy, HSC function and fate decision. More recently, we discovered that modulation of NAD cellular levels through the administration of NAD precursors entering the NAD salvage pathway (Nicotinamide riboside-NR- and nicotinamide mononucleotide-NMN-) importantly ameliorates hematopoietic stem and progenitor function and boost blood and immune recovery in bone marrow transplantation through mitophagy induction, demonstrating for the first time a link between NAD cellular levels, metabolic re-programming and fate decision. More recently we were able to demonstrate that the accumulation of dysfunctional mitochondria during aging in the hematopoietic stem cell compartment leads to impaired hematopoiesis and T cell mediated immune response. Metabolic interventions capable to induce mitochondrial recycling in “old” HSCs reestablish metabolic fitness and restore both hematopoietic and immune function.
Similarly, to what occurs during aging, we discovered that T cells in the tumor microenvironment display important mitochondrial defects that drives exhaustion features. Induction of mitochondrial recycling via NR supplementation allows the elimination of damaged mitochondria and the restoration of metabolic fitness and T cell functionality.
Overall, my studies are tackling 2 important aspects of hematological malignancies:
- We developed strategies that can boost hematopoietic recovery post bone marrow transplantation reducing the time of neutropenia exit, thus reducing the risk of infection in the post-transplant period.
- Improve the functionality of T cells which are currently use in Immunotherapy approaches for diverse hematological malignancies In this project, we intend to evaluate the cell-intrinsic effect of aging on T cell functionality which we hypothesize can reduce the efficacy of our current immunotherapeutic approaches.
We will first deeply characterised the metabolic dysfunction of ""old"" T cells and we will propose strategies that can rejuvenate old T cells for a better CAR-T cell product. Considering aging the first factor associated to Cancer, we believe that our approach can have an important impact on the current cancer immunotherapy strategies.