A single low-dose injection with anti-DLL4 in a nonhuman primate model of acute graft-vs.-host disease (aGVHD) dramatically improved post-transplant survival, providing durable protection from otherwise lethal gastrointestinal GVHD, researchers reported in the June 28, 2023, issue of Science Translational Medicine. Blocking DLL4 specifically increased the migration of beneficial regulatory T cells into the intestines, with concomitant reduction in effector T cells, which are the main culprits in aGVHD. Ultimately, these activities effectively provided protection against T-cell-mediated damage in a nonhuman macaque primate model.
The limited state of current clinical transplantation science was recently the subject of an opinion piece from an individual that received her first heart transplant at just 25 years of age only to soon succumb at the age of 60 to one of the many risky outcomes expected for anyone taking standard requisite immunosuppression regimens used for any transplantation, in her case terminal cancer.
In the March 2023 issue of Science Immunology, researchers working at the City of Hope National Medical Center reported on the discovery the mechanisms by which the spliced X-box–binding protein 1 (XBP1s) served essential functions in the IL-15-dependent survival of natural killer (NK) cells. Since XBP1s is known to play critical roles in MHCII expression, the unfolded protein stress response, and ultimately tumorigenesis, the study provided deep insights into the understanding of NK cell biology with translational potential.
The development of EGFR-targeted tyrosine kinase inhibitors (TKIs) over the past 20 years has modestly improved progression-free survival for patients with metastatic NSCLC. But many patients with EGFR mutations fail to respond to TKI treatments, and immune checkpoint inhibitors elicit a response in less than 10% of NSCLC patients.
Pancreatic cancer is an exceptionally lethal cancer that is notoriously treatment resistant, in part due to poor vascularization in the tumor microenvironment. Investigators working at the Moores Cancer Center at the University of California, San Diego (UCSD), reported in the Jan. 16, 2023, issue of Nature Cell Biology on the discovery of a pathway that was initiated by isolation stresses (e.g., hypoxia, nutrient deprivation, and/or lack of extracellular matrix, ECM) leading to this cellular transformation in the tumor-initiating pancreatic cancer cell.
The controlled cell death process of apoptosis functions as the first step to any full recovery from injury or disease. In the second step of any recovery process, dead cells are cleared by efferocytosis, a process performed by phagocytotic cells like macrophages. Approximately 200-300 billion apoptotic cells are cleared daily by efferocytosis starting with the recognition of newly extracellular facing phosphatidylserine (PtdSer) by PtdSer-binding proteins present on phagocytotic cells.
Microenvironmental factors originating from RAS-mutated cancer stem cells stimulated an angiogenic feedback loop with the surrounding environment causing the expression of leptin and TGF-β receptors on the cancer stem cells. Most significantly, leptin and TGF-β signaling were required for malignant transformation.
The findings, which were published in the Nov. 30, 2022 issue of Nature, raise “the intriguing possibility that many cancer mutations may function to lock into place, rather than set the course of, a path that is predetermined by aberrant crosstalk between a cancer stem cell and its microenvironment,” said senior author Elaine Fuchs, Rebecca C. Lancefield Professor and Howard Hughes Medical Institute investigator at Rockefeller University.
Two recent studies have reported new insights into the role of the tumor-associated microbiome in both drug response and metastasis. Researchers working at the Fred Hutchinson Cancer Center, Seattle, reported in the Nov. 16, 2022, issue of Nature that bacteria can promote the spreading of cancer as single cells with recruitment of myeloid host cells. In a parallel publication, the same team reported in the Nov. 15, 2022, issue of Cell Reports that the primary chemotherapy used to treat colorectal cancer (CRC), 5-fluorouracil (5-FU), was less effective when the tumor included bacteria that were insensitive to 5-FU antimicrobial activity.
Investigators working at University of Texas Health Science Center, Houston, have discovered that the ubiquitin ligase UBR2 is up-regulated and sufficient for targeting the myosin heavy chain protein for the degradation characteristic of cancer cachexia. UBR2 knockout or pharmacological inhibition could prevent cachexia in mice. Confirmatory observations were noted in cancer cachexia patient-derived tissues.
One way psychiatric disorders differ from neurological disorders is by the absence of anatomically defined neuropathology. “Alzheimer's disease, Parkinson's disease or stroke have a very clear picture of what cells are changing and how they're changing. The specific changes are very clear under a microscope, but in psychiatric diseases one hasn't been able to see that,” Daniel Geschwind told BioWorld.
