Cancer immunotherapy by CTLA4 blockade (WP4582)

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 [ 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 [ CTLA4 Signaling Pathway] and [ Wikipedia].
last edited


Khanspers and Fehrhart

Cited In


Homo sapiens




Disease Ontology: cancer

Cell Type Ontology: T cell professional antigen presenting cell

Pathway Ontology: adaptive immune response pathway immune response pathway cancer pathway


Label Type Compact Identifier
TCR Signaling Pathway wikipathways:WP69
PPP2CA GeneProduct ensembl:ENSG00000113575
Akt Signaling Pathway wikipathways:WP4172
Ipilimumab Metabolite wikidata:Q2459042
Tremelimumab Metabolite wikidata:Q7838098
PTPN6 GeneProduct ensembl:ENSG00000111679
CD80 GeneProduct ensembl:ENSG00000121594
CD86 GeneProduct ensembl:ENSG00000114013
Tumor-associatedantigen GeneProduct None
MHC II Protein uniprot:D7RIH8
CTLA4 GeneProduct ensembl:ENSG00000163599
TRA GeneProduct ncbigene:6955
TRB GeneProduct ncbigene:6957
CD28 GeneProduct ensembl:ENSG00000178562
PTPN11 GeneProduct ensembl:ENSG00000179295
PIK3CA GeneProduct ensembl:ENSG00000121879
PIK3R1 GeneProduct ensembl:ENSG00000145675
PIK3R2 GeneProduct ensembl:ENSG00000105647
PIK3CB GeneProduct ensembl:ENSG00000051382
PIK3CD GeneProduct ensembl:ENSG00000171608
PIK3R3 GeneProduct ensembl:ENSG00000117461


  1. Trinca C, Bressler R, Walson P. The drug surveillance program at the Arizona Medical Center. Ariz Med. 1975 Sep;32(9):702–14. PubMed Europe PMC Scholia
  2. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996 Mar 22;271(5256):1734–6. PubMed Europe PMC Scholia
  3. Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of CTLA-4 function. Annu Rev Immunol. 2006;24:65–97. PubMed Europe PMC Scholia
  4. Podojil JR, Miller SD. Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy. Immunol Rev. 2009 May;229(1):337–55. PubMed Europe PMC Scholia
  5. Dustin ML, Depoil D. New insights into the T cell synapse from single molecule techniques. Nat Rev Immunol. 2011 Sep 9;11(10):672–84. PubMed Europe PMC Scholia
  6. Walker LSK, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011 Nov 25;11(12):852–63. PubMed Europe PMC Scholia
  7. Ariyan CE, Brady MS, Siegelbaum RH, Hu J, Bello DM, Rand J, et al. Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade. Cancer Immunol Res. 2018 Feb;6(2):189–200. PubMed Europe PMC Scholia
  8. Sadreddini S, Baradaran B, Aghebati-Maleki A, Sadreddini S, Shanehbandi D, Fotouhi A, et al. Immune checkpoint blockade opens a new way to cancer immunotherapy. J Cell Physiol. 2019 Jun;234(6):8541–9. PubMed Europe PMC Scholia