Adrien KRUG

Research team

Metabolism, CAncer and immune REsponses (mCARE)

Identification of new therapeutic approaches for peripheral T lymphomas

Abstract:

Angioimmunoblastic T cell lymphoma (AITL) is an extremely rare and invasive hematological cancer for which there is currently no specific nor effective therapeutic strategy. As patient samples are extremely rare, a number of mouse models have emerged in recent years providing opportunities to study AITL. One model is the "plck-GAPDH" mouse, which overexpresses the glycolytic enzyme GAPDH exclusively in T lymphocytes, and developed a pathology equivalent to human AITL at an advanced age (18 months or more). These mice demonstrated clearly clinical signs similar to AITL, such as splenomegaly, enlarged lymph nodes and over-representation of the CD4+ PD1high CXCR5+ ICOS+ Tfh lymphocyte subpopulation, which is highly proliferative and clonal, and closely linked to germinal center B lymphocytes, also over-represented in the tumor microenvironment.

Metabolism is also an extremely important aspect of cancer, and there is growing curiosity as to its importance in tumor development and progression, and therefore its potential therapeutic targeting. The preclinical murine AITL model enabled me to identify oxidative phosphorylation as the major energy source of the CD4+ PD1high tumor cell population. Therapeutic targeting of this pathway via inhibitors of Complex I of the mitochondrial respiratory chain, such as metformin or IACS-010759, led to increased survival of mice displaying the AILT phenotype. Both drugs also eliminated the malignant CD4 T cells from the AITL patient biopsies in vitro. Combining proteomic and metabolomic analyses also highlighted the importance of lipid metabolism in this pathology. A clear increased activity of one of the branches from the Kennedy pathway was revealed next to an increased fatty acid oxidation via Beta-oxidation. The latter assures an equilibrium in global lipid metabolism, while the former leads to phosphatidylcholine production, a major lipid component of cellular membranes and essential for tumor cell proliferation. 

Inhibition of fatty acid oxidation using etomoxir, a CPT1 protein inhibitor, led to improved survival of AITL developing mice, as well as better elimination of human malignant cells in AITL patient biopsies in vitro.
In addition to metabolic targeting, gene therapy has recently provided new therapeutic strategies in oncohaematology, including the CAR T cell strategy. In this context, I have developed lentiviral vectors that target exclusively CD8 T cells for transduction (expressed by healthy cytotoxic cells) in order to let these CD8 T cells express a chimeric receptor directed against CD4 (which is present on AITL malignant cells). Thanks to this immunotherapeutic strategy, we were also able to render the CAR+ CD8 cells cytotoxic which then drastically reduced the population of malignant CD4 AITL cells in vitro.
To conclude, the AITL preclinical mouse model with a symptomatic and cellular phenotype similar to human AITL enabled us to characterize the metabolic pathway used by the tumor cells, which we were able to target effectively with inhibitors but also using a gene therapy approach such as a the CAR immunotherapy, targeted towards the AITL malignant cells.

Keywords: 

Metabolism, T-cell Lymphoma, GAPDH, AITL, CAR-T, Lipids