Abstract
Immune check point blockade therapy has revolutionized the standard of cancer treatment and is credited with producing remarkable tumor remissions and increase in overall survival. This unprecedented clinical success however is feasible for a limited number of cancer patients due to resistance occurring before or during a course of immunotherapy, which is often associated with activation of oncogenic signaling pathways, co-inhibitory checkpoints upregulation or expansion of immunosuppressive regulatory T-cells (Tregs) in the tumor microenviroment (TME). Targeted therapy aiming to inactivate a signaling pathway such as the Mitogen Activated Protein Kinases (MAPKs) has recently received a lot of attention due to emerging data from preclinical studies indicating synergy with immune checkpoint blockade therapy. The dimeric transcription factor complex Activator Protein-1 (AP-1) is a group of proteins involved in a wide array of cell processes and a critical regulator of nuclear gene expression during T-cell activation. It is also one of the downstream targets of the MAPK signaling cascade. In this review, we will attempt to unravel the roles of AP-1 in the regulation of anti-tumor immune responses, with a focus on the regulation of immune checkpoints and Tregs, seeking to extract useful insights for more efficacious immunotherapy.
Highlights
The 2018 Nobel Prize for Physiology or Medicine awarded to the pioneers of immune checkpoint research, James P
CTLA-4 cross linking on activated cells completely blocked Activator Protein-1 (AP-1) and nuclear factor of activated T-cells (NFAT) transcription factors before any effects on T cell proliferation could be observed and importantly they reported that the effect was independent of CD28 co-stimulation, suggesting that CTLA-4 inhibits the TCR signaling cascade [103]
AP-1 components (c-Jun, JunB, c-Fos, Batf) were found to transcriptionally induce the expression of genes encoding for co-inhibitory immune checkpoints (PD-1, PD-L1) via binding on the enhancer regions of the respective gene promoter
Summary
The 2018 Nobel Prize for Physiology or Medicine awarded to the pioneers of immune checkpoint research, James P. Characterized by their ability to transactivate of the MAPK pathway via a cascade of phosphorylation events on serine/threonine residues of target genes upon phorbol ester stimulation (TPA)of[26] These AP-1 transcription factors were later distinct target proteins, peaking in the activation the extracellular signal-regulated kinase (ERK), found to regulate a wide range of cellular processes spanning from cell proliferation and survival the c-Jun N-terminal kinase (JNK) and the p38 kinase. T-cell activation, TCR/CD28 signaling via PI3K and PLC (generation of Ca+2 through IP3) converge to the JNK activation which, in turn, leads to increased AP-1 activity These transcriptionally active AP-1 components, form cooperative hetero-dimers with the NFAT transcription factor and control the transactivation of key molecules involved in T-cell responses like the IL-2 gene by binding to composite DNA elements. The current viewpoint suggests that the differential expression of AP-1 components and the cell context of their interactions determines the complex functions of AP-1 transcription factor [27]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
