The role of the microbiome and leukemia-derived metabolites in regulating myeloid immune cell signaling in the tumor microenvironment

Prof. Dr. Robert Zeiser (CIBSS-AI), Department of Internal Medicine I, University Medical Center, Faculty of Medicine

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We have shown that the KRAS/NLRP3 axis promotes leukemia development (Hamarsheh et al. Nat Comm. 2020) and that lactic acid (LA) derived from leukemia cells leads to metabolic reprogramming of T cells (Uhl et al. Sci Transl Med. 2020). We observed that metabolic reprogramming by sodium bicarbonate (NaBi) reversed the LA-induced low intracellular pH, restored metabolite concentrations, led to incorporation of LA into the tricarboxylic acid cycle as an additional energy source, and enhanced anti-leukemia activity of murine and human T cells. Our preliminary data indicate that LA reduces MEK/ERK signalling in T cells. We plan to investigate in an unbiased approach which signalling pathways are affected by leukemia cells in T cells and myeloid cells. We plan to study if anti-PD1 and anti-TIM3 immunotherapy can reverse leukemia induced signalling and effector function defects in T cells and myeloid cells.