Metabolic interventions in chronic lymphocytic leukemia Towards tumor elimination and immune rejuvenation

Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, remains incurable despite significant treatment advances. Targeted therapies, such as venetoclax + ibrutinib, directed at killing malignant cells, face the emergence of resistance, due to microenvironmental protective stimuli and genetic mutations (e.g. TP53). T-cell based immunotherapies show poor responses due to the acquired T-cell dysfunction of CLL patients.
This thesis explores the effects of metabolic interventions in relation to two key aspects of CLL biology. The first part of the thesis focuses on unravelling the interplay between metabolic reprogramming of CLL cells and drug resistance. First, we exploit glutamine (Gln) dependency of CLL cells as a metabolic vulnerability to counteract microenvironmental-induced venetoclax resistance. Furthermore, the thesis explores the impact of disrupting Gln metabolism on TP53 dysfunctional cells.
The second part of the thesis focuses on the interplay between metabolic impairment and T-cell dysfunction. Our study highlights that CLL cells induce pseudohypoxia, impaired mitochondrial metabolism and the production of immunosuppressive adenosine by the surrounding T cells. Next, a critical re-evaluation of T-cell dysfunction in CLL challenges its definition as (pseudo-)exhaustion, revealing a prevalence of senescent T cells. Intriguingly, the removal of CLL cells restores metabolic function and reverses senescent features.
In conclusion, this thesis underscores the feasibility of metabolic interventions in CLL as adjuvant strategies to eliminate malignant cells while rejuvenating the T cells, opening avenues for novel therapeutic approaches.