Ultrasound May Suppress Tumor Growth, Inhibit Inflammation, and Establish Tolerogenesis by Remodeling Innatome via Pathways of ROS, Immune Checkpoints, Cytokines, and Trained Immunity/Tolerance.

Qian Yang,Charles Drummer,Jason Saredy,Fatma Saaoud,Shuping Ge,Ruijing Zhang,Xiaofeng Yang,Yifan Lu,Xiaohua Jiang,Daohai Yu,Ying Shao,Rongshan Li,Peng Tang,Candice Johnson,Keman Xu,Susu Wu,Jiwei Wang,Yu Sun,Hong Wang

doi:10.1155/2021/6664453

Abstract

Background The immune mechanisms underlying low-intensity ultrasound- (LIUS-) mediated suppression of inflammation and tumorigenesis remain poorly determined. Methods We used microarray datasets from the NCBI GEO DataSet repository and conducted comprehensive data-mining analyses, where we examined the gene expression of 1376 innate immune regulators (innatome genes (IGs) in cells treated with LIUS. Results We made the following findings: (1) LIUS upregulates proinflammatory IGs and downregulates metastasis genes in cancer cells, and LIUS upregulates adaptive immunity pathways but inhibits danger-sensing and inflammation pathways and promote tolerogenic differentiation in bone marrow (BM) cells. (2) LIUS upregulates IGs encoded for proteins localized in the cytoplasm, extracellular space, and others, but downregulates IG proteins localized in nuclear and plasma membranes, and LIUS downregulates phosphatases. (3) LIUS-modulated IGs act partially via several important pathways of reactive oxygen species (ROS), reverse signaling of immune checkpoint receptors B7-H4 and BTNL2, inflammatory cytokines, and static or oscillatory shear stress and heat generation, among which ROS is a dominant mechanism. (4) LIUS upregulates trained immunity enzymes in lymphoma cells and downregulates trained immunity enzymes and presumably establishes trained tolerance in BM cells. (5) LIUS modulates chromatin long-range interactions to differentially regulate IGs expression in cancer cells and noncancer cells. Conclusions Our analysis suggests novel molecular mechanisms that are utilized by LIUS to induce tumor suppression and inflammation inhibition. Our findings may lead to development of new treatment protocols for cancers and chronic inflammation.

Highlights

Ultrasound, alone or combined with contrast agent microbubbles, has numerous applications, which range from being well-established diagnostic tools [1, 2] to methods of drug delivery [3]
We found three microarray datasets deposited in the National Institutes of Health- (NIH-)National Center for Biotechnology Information (NCBI) GEO DataSet repository, which depicted human lymphoma cells and noncancer mouse MC3T3-E1 preosteoblast cells and rat bone marrow (BM) cells that were treated with low-intensity ultrasound (LIUS) (Table 1)
One of the 14 functional groups of innatomic genes (IGs) was significantly downregulated from 1.6% in the general innatome to 1.3% in lymphoma cells and 0.93% in BM cells but was not changed in preosteoblast cells. These results have demonstrated that first, LIUS differentially upregulates more IGs encoded for proteins localized in three out of five subcellular locations such as the cytoplasm, extracellular space, and other subcellular localizations, but downregulates more IGs encoded for proteins localized in the nucleus and plasma membrane subcellular locations, suggesting that LIUS has specific effects on different subcellular localized innatome proteins; second, LIUS downregulates more phosphatases than the other 13 functional subgroups; and third, since downregulation of phosphatases appear to be a consequence of LIUS treatment, downregulation of phosphatases may serve as a clinical efficacy marker for LIUS therapies

Summary

Introduction

Ultrasound, alone or combined with contrast agent microbubbles, has numerous applications, which range from being well-established diagnostic tools [1, 2] to methods of drug delivery [3]. Recent reports showed that utilization of ultrasound contrast microbubbles causes the so-called “sonoporation” effect [4, 5], which has been recognized to cause transient disruption of cellular membranes [6], allowing more accessible transport of extracellular compounds into the cytoplasm of viable cells [7]. The immune mechanisms underlying low-intensity ultrasound- (LIUS-) mediated suppression of inflammation and tumorigenesis remain poorly determined. We made the following findings: (1) LIUS upregulates proinflammatory IGs and downregulates metastasis genes in cancer cells, and LIUS upregulates adaptive immunity pathways but inhibits danger-sensing and inflammation pathways and promote tolerogenic differentiation in bone marrow (BM) cells. Our findings may lead to development of new treatment protocols for cancers and chronic inflammation

Methods

Results

Conclusion