Background: Although checkpoint-based immunotherapy has shown exciting results in the treatment of tumors, around 70% of patients have experienced unresponsiveness. PVRIG is a recently identified immune checkpoint receptor and blockade of which could reverse T cell exhaustion to treat murine tumor; however, its therapeutic potential via NK cells in mice and human remains seldom reported.
Methods: In this study, we used patient paraffin-embedded colon adenocarcinoma sections, various murine tumor models (MC38 colon cancer, MCA205 fibrosarcoma and LLC lung cancer), and human NK cell- or PBMC-reconstituted xenograft models (SW620 colon cancer) to investigate the effect of PVRIG on tumor progression.
Results: We found that PVRIG was highly expressed on tumor-infiltrating NK cells with exhausted phenotype. Furthermore, either PVRIG deficiency, early blockade or late blockade of PVRIG slowed tumor growth and prolonged survival of tumor-bearing mice by inhibiting exhaustion of NK cells as well as CD8 T cells. Combined blockade of PVRIG and PD-L1 showed better effect in controlling tumor growth than using either one alone. Depletion of NK or/and CD8 T cells in vivo showed that both cell types contributed to the anti-tumor efficacy of PVRIG blockade. By using Rag1 mice, we demonstrated that PVRIG blockade could provide therapeutic effect in the absence of adaptive immunity. Further, blockade of human PVRIG with monoclonal antibody enhanced human NK cell function and inhibited human tumor growth in NK cell- or PBMC-reconstituted xenograft mice.
Conclusions: Our results reveal the importance of NK cells and provide novel knowledge for clinical application of PVRIG-targeted drugs in future.
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http://dx.doi.org/10.1186/s13045-021-01112-3 | DOI Listing |
JAMA Netw Open
January 2025
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston.
Importance: Cardiovascular disease (CVD) and cancer are the leading causes of mortality in the US. Large-scale population-based and mechanistic studies support a direct effect of CVD on accelerated tumor growth and spread, specifically in breast cancer.
Objective: To assess whether individuals presenting with advanced breast cancers are more likely to have prevalent CVD compared with those with early-stage breast cancers at the time of diagnosis.
Vet Med Sci
January 2025
Department of Medical Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
The present study aimed to unveil the gastroprotective potential of Vaccinium macrocarpon (VM) extract and its mechanism of action against indomethacin (INDO)-induced gastric ulcers in rats. To achieve this goal, rats were pretreated with either omeprazole (20 mg/kg) or VM (100 mg/kg) orally for 14 consecutive days. Gastric tissue samples were collected and various parameters were evaluated to understand the mechanism of VM's action, including the levels of superoxide dismutase, malondialdehyde, glutathione, CAT and transforming growth factor beta (TGF-β), as well as the mRNA expression levels of tumour necrosis factor alpha, interleukin 1 beta, nuclear factor kappa B (NF-κB) and inhibitor kappa B (IκB).
View Article and Find Full Text PDFCancer Immunol Res
January 2025
Massachusetts Institute of Technology, Cambridge, MA, United States.
Tumor cell-intrinsic signaling pathways can drastically affect the tumor immune microenvironment, promoting tumor progression and resistance to immunotherapy by excluding immune-cell populations from the tumor. Several tumor cell-intrinsic pathways have been reported to modulate myeloid-cell and T-cell infiltration creating "cold" tumors. However, clinical evidence suggests that excluding cytotoxic T cells from the tumor core also mediates immune evasion.
View Article and Find Full Text PDFCancer Res
January 2025
University of California, San Diego, La Jolla, CA, United States.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as a super enhancer-associated gene in human PDAC, which encodes the flavin monooxygenase MICAL2 that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin-related transcription factors (MRTF-A and MRTF-B).
View Article and Find Full Text PDFJ Agric Food Chem
January 2025
CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Nanhai Road 7, Qingdao 266071, China.
Ten cytochalasin derivatives, including six new methylthioether-containing chaetoglobosins (thiochaetoglobosins A-F, ), a new related congener (18-nor-prochaetoglobosin II, ), and three known unsulfured counterparts (), were isolated and identified from AS-506, an endozoic fungus isolated from a deep-sea sponge, which was collected from Magellan Seamounts in the Western Pacific Ocean. Their structures were determined by extensive interpretation of the spectroscopic and X-ray crystallographic data, as well as by ECD calculations. Structurally, thiochaetoglobosins A-F () represent the first examples of chaetoglobosin derivatives containing a methylthioether group in the molecules, while 18-nor-prochaetoglobosin II () is the first 18-nor-chaetoglobosin derivative.
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