Cancer immunotherapy by CTLA4 blockade (WP4582)
Homo sapiens
Immune checkpoints are hardwired into the immune system and are crucial for maintaining self-tolerance. Tumors can use these checkpoints to protect themselves from immune system attacks. CTLA-4 is expressed on T cells and is a negative regulator of T cell activation. CTLA4 counteracts the activity of the T cell co-stimulatory receptor, CD28, which amplifies TCR signaling once antigen is bound. CTLA-4 and CD28 share the same ligands, CD80 and CD86, although CTLA-4 has a higher affinity. This is represented in the pathway with a blue inhibitory interaction. One strategy for cancer immunotherapy is to block CTLA-4, thereby removing the negative regulation on T-cell activation. The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of melanoma. The [https://www.nobelprize.org/prizes/medicine/2018/summary/ 2018 Nobel prize in Physiology or Medicine] was awarded to jointly to James Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation. Partially based on Thermo Fisher [https://www.thermofisher.com/us/en/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/cell-signaling-pathways/ctla4-signaling-pathway.html CTLA4 Signaling Pathway] and [https://en.wikipedia.org/wiki/Immune_checkpoint Wikipedia].
Authors
Kristina Hanspers , Friederike Ehrhart , Egon Willighagen , and Eric WeitzActivity
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Cited In
- An NF-κB- and Therapy-Related Regulatory Network in Glioma: A Potential Mechanism of Action for Natural Antiglioma Agents (2022).
- DNA methylation of ARHGAP30 is negatively associated with ARHGAP30 expression in lung adenocarcinoma, which reduces tumor immunity and is detrimental to patient survival (2021).
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Organisms
Homo sapiensCommunities
CPTACAnnotations
Cell Type Ontology
professional antigen presenting cell T cellPathway Ontology
cancer pathway immune response pathway adaptive immune response pathwayDisease Ontology
cancer| Label | Type | Compact URI | Comment |
|---|---|---|---|
| Ipilimumab | Metabolite | wikidata:Q2459042 | |
| Tremelimumab | Metabolite | wikidata:Q7838098 | |
| PPP2CA | GeneProduct | ensembl:ENSG00000113575 | |
| PTPN6 | GeneProduct | ensembl:ENSG00000111679 | |
| CD80 | GeneProduct | ensembl:ENSG00000121594 | |
| CD86 | GeneProduct | ensembl:ENSG00000114013 | |
| CTLA4 | GeneProduct | ensembl:ENSG00000163599 | |
| TRA | GeneProduct | ncbigene:6955 | |
| TRB | GeneProduct | ncbigene:6957 | |
| CD28 | GeneProduct | ensembl:ENSG00000178562 | |
| PTPN11 | GeneProduct | ensembl:ENSG00000179295 | |
| PIK3CA | GeneProduct | ensembl:ENSG00000121879 | Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18706 |
| PIK3R1 | GeneProduct | ensembl:ENSG00000145675 | Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18708 |
| PIK3R2 | GeneProduct | ensembl:ENSG00000105647 | Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18709 |
| PIK3CB | GeneProduct | ensembl:ENSG00000051382 | Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:74769 |
| PIK3CD | GeneProduct | ensembl:ENSG00000171608 | Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18707 |
| PIK3R3 | GeneProduct | ensembl:ENSG00000117461 | Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:75669 |
| MHC II | Protein | uniprot:D7RIH8 |
References
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- Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy. Podojil JR, Miller SD. Immunol Rev. 2009 May;229(1):337–55. PubMed Europe PMC Scholia
- New insights into the T cell synapse from single molecule techniques. Dustin ML, Depoil D. Nat Rev Immunol. 2011 Sep 9;11(10):672–84. PubMed Europe PMC Scholia
- The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Walker LSK, Sansom DM. Nat Rev Immunol. 2011 Nov 25;11(12):852–63. PubMed Europe PMC Scholia
- Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade. Ariyan CE, Brady MS, Siegelbaum RH, Hu J, Bello DM, Rand J, et al. Cancer Immunol Res. 2018 Feb;6(2):189–200. PubMed Europe PMC Scholia
- Immune checkpoint blockade opens a new way to cancer immunotherapy. Sadreddini S, Baradaran B, Aghebati-Maleki A, Sadreddini S, Shanehbandi D, Fotouhi A, et al. J Cell Physiol. 2019 Jun;234(6):8541–9. PubMed Europe PMC Scholia