Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for STAT3's mitochondrial functions. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also result in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML.

Bacterial infections can induce exuberant immune responses that can damage host tissues. Previously, we demonstrated that systemic Escherichia coli infection in mice causes tissue damage in the liver. This liver necrosis is associated with the expression of endogenous retroviruses, chromosomally integrated retroviruses that encode a reverse transcriptase. Furthermore, nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) completely prevent tissue damage and subsequent bacterial growth within necrotic lesions. Since liver necrosis is linked to heightened systemic inflammatory responses, we hypothesized that NRTIs diminish inflammation caused by E. coli infection and may also have broad impacts on the systemic immune response to bacterial pathogens. Here, we tested this hypothesis by characterizing the effects of NRTIs on the innate immune response to bacteria. In the liver, NRTI administration following E. coli inoculation reduced the expression of a large repertoire of proinflammatory transcripts. NRTIs also had systemic anti-inflammatory effects, including reducing proinflammatory cytokine levels in serum in response to E. coli in different mouse strains. The anti-inflammatory effects of NRTIs were also apparent in response to lipopolysaccharide (LPS) and Staphylococcus aureus, suggesting that the molecular mechanisms underlying the immunomodulatory functions of NRTIs are likely conserved across distinct immune signaling pathways. Moreover, in a model of lethal LPS shock, NRTI administration prevented hypothermia and death. Together, our observations reveal that NRTIs can potently impede systemic inflammatory responses during Gram-positive and Gram-negative bacterial infections. Our findings lay the groundwork for further investigation of the therapeutic scope of NRTIs and the mechanisms underlying their anti-inflammatory effects across non-retroviral infectious diseases.IMPORTANCEInflammatory responses are critical for host control of bacterial infection, but excessive inflammation can damage host tissues and lead to sepsis. Understanding how innate immune responses are controlled during infection is important for developing new approaches to dampen excessive inflammation. In previous work, we found that tissue damage caused by excessive inflammatory responses may be driven by endogenous reverse transcriptases. Here we demonstrate that treatment of mice with reverse transcriptase inhibitors leads to broad reductions in systemic proinflammatory responses during bacterial infections and can protect mice from acute death in a lethal model of sepsis. Our findings indicate that uncovering the mechanisms underlying the anti-inflammatory functions of reverse transcriptase inhibitors may lead to new therapeutics for bacterial infectious diseases.

Partial stereotactic body radiation therapy (SBRT) targeting hypoxic regions of large tumors (SBRT-PATHY) has been shown to enhance the efficacy of tumor radiotherapy by harnessing the radiation-induced immune response. This approach suggests that reducing the irradiation target volume not only achieves effective anti-tumor effects but also minimizes damage to surrounding normal tissues. In this study, we evaluated the antitumor efficacy of reduced-tumour-area radiotherapy (RTRT) , and explored the relationship between tumor control and immune preservation and the molecular mechanisms underlying of them.
In mouse breast cancer models, we compared the anti-tumor effects of RTRT and conventional radiotherapy (CNRT) by assessing tumor growth, metastasis, and survival rates. Additionally, we evaluated the peritumoral tissue damage and the immune microenvironment. The maturation of dendritic cells (DCs) and DNA damage induced by irradiated tumor cells were also assessed in vitro.
In pre-clinical models, both RTRT and CNRT significantly inhibited primary tumor growth when compared to non-irradiated controls, with no significant difference between RTRT and CNRT. However, RTRT significantly extended survival times in mice, and increased the likelihood of inducing abscopal effects, thereby providing potential for better control of distant metastases. Further investigations revealed that the enhanced efficacy of RTRT may be attributed to the preservation of lymphocytes within the peritumoral tissue, as well as reduced damage to the surrounding skin and circulating lymphocytes. In vitro assays demonstrated that RTRT induced DNA damage and dsDNA in tumor cells, activating the cGAS-STING pathway. RTRT also triggered the release of damage-associated molecular patterns (DAMPs), which synergistically amplified the anti-tumor immune response.
Our findings suggested that appropriately narrowing the irradiation target volume effectively killed tumor cells while reducing damage to surrounding tissues, and preserving peritumoral lymphocytes. This approach improved the safety of radiotherapy while maintaining its efficacy in tumor control and provided an opportunity for combining high-dose radiotherapy with immunotherapy.
© 2024. The Author(s).

Abstract The effect of increased triglycerides (TGs) as an independent factor in atherosclerosis development has been contentious, in part, because severe hypertriglyceridemia associates with low levels of low-density lipoprotein cholesterol (LDL-C). To test whether hyperchylomicronemia, in the absence of markedly reduced LDL-C levels, contributes to atherosclerosis, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl-/-) and LDLR knockdown (Ldlrkd) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL. After 12 weeks on a WD, atherosclerotic lesions both in the brachiocephalic artery and the aortic root were more severe in iLpl-/-/Ldlrkd mice compared to the control Ldlrkd mice. One likely mechanism for this is that exposure of the aorta to hyperchylomicronemia led endothelial cell inflammation. Thus, our data show that intact chylomicrons contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease, and prove that hyperchylomicronemia is not benign.

Type 2 innate lymphoid cells (ILC2s) are crucial in regulating immune responses and various physiological processes, including tissue repair, metabolic homeostasis, inflammation, and cancer surveillance. Here, we present a protocol that outlines the isolation, expansion, and adoptive transfer of human ILC2s from peripheral blood mononuclear cells for an in vivo lineage tracking experiment in a mouse model. Additionally, we detail the steps involved in the adoptive transfer of human ILC2s to recipient mice bearing human liquid or solid tumors. For complete details on the use and execution of this protocol, please refer to Li et al.1.
Copyright © 2024. Published by Elsevier Inc.