Figure 7.

(a) LIUS upregulated trained immunity enzymes in lymphoma cells and downregulated trained immunity enzymes in bone marrow cells, suggesting that LIUS enhances innate immune responses in cancer cells and inhibits innate immune responses in noncancer cells, which are associated with its modulation of trained immunity enzyme expressions. By analyzing microarray data of LIUS-treated human lymphoma cells, mouse preosteoblasts, and rat bone marrow cells, we examined a novel hypothesis that LIUS induces its therapeutic effects in cells by modulating the expressions of our newly reported (PMID: 31153039) innate immune memory (trained immunity) pathway enzymes. Our results show that LIUS downregulates 12 out of 102 trained immunity genes, including 11 (10.8%) in bone marrow cells and one in lymphoma cells. In addition, LIUS induces 11 out of 102 trained immunity genes (10.8%) including 6 in lymphoma cells, 1 in preosteoblasts, and 4 in bone marrow cells. Moreover, in bone marrow cells, LIUS upregulates 4 trained immunity genes and downregulates 11 trained immunity genes including 8 glycolysis enzymes, one acetyl-CoA enzyme, and two mevalonate pathway enzymes, suggesting that 2.75-fold more downregulation than upregulation of trained immunity genes in bone marrow cells contributes significantly to LIUS-suppressed innate immunity and inflammation. Finally, in contrast, in lymphoma cells, LIUS upregulation of six trained immunity enzymes including 5 glycolysis enzymes and one acetyl-CoA generation enzymes and downregulation of one glycolysis enzyme in lymphoma cells (6-fold more upregulation than downregulation) contribute significantly to LIUS-induced innate immunity enhancement. (b) Low-intensity ultrasound (LIUS) therapy upregulated trained immunity enzymes (PMID: 27102489) in lymphoma cells and downregulated trained immunity enzymes in bone marrow cells. These results suggest that LIUS enhances antitumor immune responses against lymphoma cells at least partially by upregulating trained immunity pathways, which is similar to that proposed by others (PMID: 27903713); LIUS also inhibits inflammation in noncancer cells by suppressing trained immunity pathways (see our recent report, PMID: 31153039). Trained immunity (innate immune memory): newly characterized adaptive metabolic and epigenetic remodeling of innate immune cells including (1) upregulation of glycolysis pathway enzymes, (2) increased acetyl-CoA generation, (3) upregulation of mevalonate pathway enzymes, and (4) remodeling of histone methylation and acetylation.