Mitochondrial reprogramming to restore age-driven metabolic dysfuntion and boost Immunotherapy
Description: Immunotherapy has emerged as a key therapeutic strategy for cancer treatment. The success of CD19-directed CAR-T cells on haematological malignancies has generated a wide interest to translate this approach to treat solid tumors. However, the clinical outcomes in this context have been unexpectedly poor due to both extrinsic and intrinsic suppressive factors that drive T cell dysfunction within the tumor microenvironment (TME). A fundamental characteristic that contributes to anti-tumor T cell functionality is the maintenance of mitochondrial fitness, which has been shown to sustain memory/stem-like properties and provide prolonged T cell responses. Even though mitochondrial dysfunction is a hallmark of aging, how age-associated alterations of immune metabolism affect the outcome of Immunotherapy remains poorly understood. Our preliminary data demonstrate that aging leads to the overexpression of CD38 in T cells that, in turn, drives mitochondrial and functional defects. CD38 is a NAD consuming enzyme which has been associated with aging and T cell exhaustion. We demonstrated that NAD decline is mediating the CD38-driven mitochondrial and functional defects in T cells. Here we propose to elucidate the role of aging and cellular mechanisms driving NAD decline as contributors of immunotherapy failure and propose strategies to rejuvenate old T cell with the final aim to improve cancer immunotherapy. Moreover, we intend to characterize the changes occurring in the TME during aging. We hypothesize that an “old” TME will pose further immunological barriers to immunotherapy, and features of an “old” TME would be associable to a non-responsive tumor.Our work proposes a model where the age-driven NAD decline and mitochondrial dysfunction in old CD8+ T lymphocytes leads to limited acquisition of memory characteristics. Overall, we believe that tackling the mechanisms of age-driven dysfunction in T cells would open the way for the application of novel strategies to boost immunotherapy in older adults.
Amount: CHF 800,000
Funding type: research
Funder scheme: Project funding
Start date: 2025-01-01
End date: 2028-12-31
Investigator: Vannini, Nicola
Institution: University of Fribourg – FR
Funded outputs count: 1
Funder award ID: 10002388
OpenAlex ID: G2094567323