Metabolic Reprogramming Overcomes T Cell Inhibition By AML Cells

Allogeneic hematopoietic cell transplantation (allo-HCT) is the treatment strategy of choice for the majority of patients with acute myeloid leukemia (AML). However, about 40% of patients relapse, which is associated with a poor prognosis. Donor lymphocyte infusions (DLIs) induce remission only in a minority of relapsed AML patients.

In order to understand the impact of AML cells on T cell bioenergetics, we investigated the metabolic phenotype and immunological profile of CD8⁺ T cells isolated from AML patients at primary diagnosis, during remission and relapse after allo-HCT. At diagnosis, T cells exhibited robust metabolic activity and strong immune activation. In contrast, during relapse, T cells demonstrated reduced glycolytic and respiratory activity compared to their status at remission. The metabolic phenotype was accompanied by reduced cytotoxic ability. Metabolomics revealed lactate accumulation and substantial arginine depletion in the serum of these patients.

The results observed in the human setting could be reproduced in a murine graft versus leukemia (GVL) model where T cells isolated from AML bearing mice exhibited lower metabolic activity compared to control animals.

In vitro co-culture experiments enabled tightly controlled conditions for mechanistic studies. The metabolic impairment induced by AML cells was mediated by soluble factors, mirroring the major changes in serum metabolites of patients, and interfered with the crucial metabolic reprogramming in the priming phase of T cells. Well-known mechanisms such as nutrient deprivation could be excluded. Extensive transcriptomic and metabolomic analyses have been undertaken in order to identify the molecules responsible for the diminished metabolic activation.

Influencing mitochondrial architecture thereby boosting respiratory activity prior to infusion led to enhanced anti-leukemic activity of T cells in vivo. The pre-treatment favored an immunological memory phenotype essential for a potent GVL effect. Using metabolic stimuli as pre-treatment of DLIs could promote T cell resistance against tumor evasion and increase anti-tumor immunity. This could greatly improve the success of DLIs and other adoptive T cell transfer strategies in the treatment of AML relapse.