TMIC-38. MODULATION OF CANCER CELL METABOLISM AND IMMUNE PHENOTYPE BY TTFIELDS

Abstract

Therapeutic low dose alternating electric fields (TTFields) have been demonstrated to disrupt cells during mitosis leading to aberrant mitotic exit. Cells exposed to TTFields exhibit evidence of endoplasmic reticulum stress, surface expression of immune stimulatory stress marker proteins calreticulin, and the secretion of the Alarmin/DAMP protein, HMGB1. Co-culture of bone marrow derived macrophages with TTFields-treated CT26 cells resulted in the up-regulation of cell surface activation markers that was reversed by the addition of anti-HMGB1 antibodies. Macrophages co-cultured with TTFields-exposed cells also produced increased levels of pro-inflammatory chemokines and the reduction of anti-inflammatory cytokines, further supporting the hypothesis that TTFields induce anti-tumor immunity as part of their mechanism of action. In addition, cells exposed to TTFields exhibited reductions in levels of culture media acidification. Analysis of intracellular metabolites showed evidence for an increase in mitochondrial respiration products, including increased ATP, GTP and phosphocreatine as well as increases in early intermediates from the glycolysis and glutaminolysis pathways. These metabolic changes are consistent with a decreased requirement for lactate production. Exposure to both increased levels of lactate and low pH have been demonstrated to influence the differentiation and stabilization of immunosuppressive subsets of both myeloid and lymphoid cells that promote immune tolerance needed for tumor immune evasion. Thus, low pH within the tumor likely contributes to tumor aggressiveness and has been correlated with poor clinical outcome in glioma patients. Analysis of urine from TTFields-treated patient revealed a correlation between low pH and poor clinical outcome in TTFields-treated patients. Together, these data suggests a novel mechanism by which TTFields increase tumor cell immunogenicity and alter cancer cell metabolism which perturbs immune suppressive functions within the tumor microenvironment facilitating immune recognition and rejection. This model of TTFields action may provide an additional basis to improve treatment efficacy.