Antagonistic antibodies targeting the inhibitory immune-checkpoint receptor PD-1 or its ligand PD-L1 are used to treat a wide range of cancer types and can substantially improve patient survival. Nevertheless, strategies to overcome intrinsic and acquired resistance are required to respectively increase response rates and durations. PD-L1 is often upregulated in various malignancies, and emerging evidence suggests numerous underlying mechanisms involving distinct oncogenic signalling pathways. Thus, specific small-molecule inhibitors have the potential to simultaneously suppress not only a key oncogenic signalling pathway but also PD-L1 expression and/or activity in particular cancers, thereby presenting attractive candidate drugs for combination with existing immune-checkpoint inhibitors and/or other targeted agents. Herein, we summarize advances in understanding the mechanisms regulating PD-L1 expression at the transcriptional, post-transcriptional, translational and post-translational levels in cancers. We describe the roles of the diverse post-translational modifications of PD-L1, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination. Moreover, we discuss the potential use of small-molecule agents to modulate these mechanisms as well as of predictive biomarkers to stratify patients for optimal treatment, and provide our perspective on potential therapeutic strategies to circumvent resistance to conventional anti-PD-1/PD-L1 antibodies.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1038/s41571-022-00601-9 | DOI Listing |
Purpose: Outcomes for patients with advanced sarcomas are poor and there is a high unmet need to develop novel therapies. The purpose of this phase I study was to define the safety and efficacy of botensilimab (BOT), an Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody, plus balstilimab (BAL), an anti-PD-1 antibody, in advanced sarcomas.
Methods: BOT was administered intravenously (IV) at 1 mg/kg or 2 mg/kg once every 6 weeks in combination with BAL IV at 3 mg/kg once every 2 weeks for up to 2 years.
Mol Pharm
January 2025
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
The fungal metabolite verticillin A is a potent and selective histone methyltransferase inhibitor. It regulates apoptosis, the cell cycle, and stress response, and displays potent activity in the suppression of tumor cell growth in several different in vivo models. Verticillin A sensitizes pancreatic cancer cells to anti-PD-1 immunotherapy by regulating PD-L1 expression.
View Article and Find Full Text PDFFront Immunol
January 2025
Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Background: Bladder cancer (BCa) is one of the most common malignancies worldwide, and its prognostication and treatment remains challenging. The fast growth of various cancer cells requires reprogramming of its energy metabolism using aerobic glycolysis as a major energy source. However, the prognostic and therapeutic value of glycolysis-related genes in BCa remains to be determined.
View Article and Find Full Text PDFToxicol Res (Camb)
February 2025
Respiratory Medicine, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, 71 Baoshan North Road, Yunyan District, Guiyang Guizhou 550001, China.
To examine the therapeutic effectiveness and safety of traditional Chinese medicine in conjunction with PD-1/PD-L1 inhibitors for nourishing yin and replenishing qi in patients with non-small cell lung cancer. A systematic search was conducted across seven electronic databases, namely PubMed, Cochrane Library, Excerpt Medica Database, Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and Wan-fang Database, to identify eligible studies from 2,000 to 2,023. This study includes a total of 14 randomized controlled clinical trials, with 514 patients in the TCM combo therapy group and 506 patients in the control group.
View Article and Find Full Text PDFImmunotargets Ther
January 2025
Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, People's Republic of China.
Purpose: Our previous study has demonstrated that high expression of immune checkpoints (ICs) was significantly associated with adverse clinical outcomes in patients with acute myeloid leukemia (AML). This study aims to investigate the significance of the alteration of IC co-expression for evaluating the prognosis of AML patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Patients And Methods: Quantitative real-time PCR (qRT-PCR) data of bone marrow (BM) samples from 62 de novo AML patients, including 37 patients who received allo-HSCT and 25 patients who received chemotherapy only, were used for prognostic analysis.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!