Lymphocyte Exhaustion in AML Patients and Impacts of HMA/Venetoclax or Intensive Chemotherapy on Their Biology.

Acute myeloid leukemia (AML) is an aggressive malignancy that requires rapid treatment with chemotherapies to reduce tumor burden. However, these chemotherapies can compromise lymphocyte function, thereby hindering normal anti-tumor immune responses and likely limiting the efficacy of subsequent immunotherapy. To better understand these negative impacts, we assessed the immunological effects of standard-of-care AML therapies on lymphocyte phenotype and function over time. When compared to healthy donors, untreated AML patients showed evidence of lymphocyte activation and exhaustion and had more prevalent CD57+NKG2C+ adaptive NK cells, which was independent of human cytomegalovirus (HCMV) status. HMA/venetoclax treatment resulted in a greater fraction of T cells with effector memory phenotype, inhibited IFN-γ secretion by CD8+ T cells, upregulated perforin expression in NK cells, downregulated PD-1 and 2B4 expression on CD4+ T cells, and stimulated Treg proliferation and CTLA-4 expression. Additionally, we showed increased expression of perforin and CD39 and enhanced IFN-γ production by T cells from pre-treatment blood samples of venetoclax-resistant AML patients. Our results provide insight into the lymphocyte status in previously untreated AML patients and the effects of standard-of-care treatments on their biology and functions. We also found novel pre-treatment characteristics of T cells that could potentially predict venetoclax resistance.

IL-27 receptor-regulated stress myelopoiesis drives abdominal aortic aneurysm development.

Abdominal aortic aneurysm (AAA) is a prevalent life-threatening disease, where aortic wall degradation is mediated by accumulated immune cells. Although cytokines regulate inflammation within the aorta, their contribution to AAA via distant alterations, particularly in the control of hematopoietic stem cell (HSC) differentiation, remains poorly defined. Here we report a pathogenic role for the interleukin-27 receptor (IL-27R) in AAA, as genetic ablation of IL-27R protects mice from the disease development. Mitigation of AAA is associated with a blunted accumulation of myeloid cells in the aorta due to the attenuation of Angiotensin II (Ang II)-induced HSC expansion. IL-27R signaling is required to induce transcriptional programming to overcome HSC quiescence and increase differentiation and output of mature myeloid cells in response to stress stimuli to promote their accumulation in the diseased aorta. Overall, our studies illuminate how a prominent vascular disease can be distantly driven by a cytokine-dependent regulation of bone marrow precursors.

The effect of lornoxicam on TLR2 and TLR4 messenger RNA expression and tumor necrosis factor-α, interleukin-6, and interleukin-8 secretion in patients with systemic complications of acute pancreatitis.

OBJECTIVES: To assess the effects of the cyclooxygenase-1/cyclooxygenase-2 inhibitor lornoxicam on systemic complications in patients with acute pancreatitis, Toll-like receptor (TLR)2 and TLR4 messenger RNA expression, and cytokine secretion (IL-6, IL-8, tumor necrosis factor-α). METHODS: Adult patients with acute pancreatitis were randomized to standard therapy or standard therapy plus lornoxicam. Standard therapy included analgesics, spasmolytics, octreotide, pantoprazole, and intravenous fluids. The TLR2 and TLR4 expression levels and TLR2- and TLR4-mediated cytokine production in peripheral blood mononuclear cells were assessed in patients with severe complications and in healthy volunteers (n = 15). RESULTS: A total of 334 patients received standard therapy (n = 246) or standard therapy plus lornoxicam (n = 88), 172 (51.5%) of whom developed systemic complications. Occurrence of complications was higher with standard therapy compared with lornoxicam (57.3% versus 35.2%; P = 0.00034), as was mortality (19.1% versus 6.8%; P = 0.006). The TLR2 and TLR4 expression and TLR2 and TLR4-mediated cytokine production were significantly higher in patients with systemic complications of acute pancreatitis compared with healthy volunteers. Relative TLR2 expression and cytokine production were significantly reduced in patients receiving lornoxicam versus standard therapy. CONCLUSIONS: The use of lornoxicam at the onset of acute pancreatitis decreased TLR2 and TLR4 expression and the production of proinflammatory cytokines, thereby reducing the risk of systemic complications and mortality.