Cancer immunotherapy by CTLA4 blockade (Homo sapiens)

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1, 462, 5, 73, 83, 8LegendAPCAntagonistic bindingIL-2 expressionImmune ResponseCD80IpilimumabTremelimumabAkt SignalingPPP2CATCR SignalingPTPN6CD86Tumor-associatedantigenMHC IIT cellCTLA4TRATRBCD28PTPN11PIK3CAPIK3R1PIK3R2PIK3CBPIK3CDPIK3R3


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.

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  1. Leach DR, Krummel MF, Allison JP; ''Enhancement of antitumor immunity by CTLA-4 blockade.''; Science, 1996 PubMed Europe PMC
  2. Teft WA, Kirchhof MG, Madrenas J; ''A molecular perspective of CTLA-4 function.''; Annu Rev Immunol, 2006 PubMed Europe PMC
  3. Dustin ML, Depoil D; ''New insights into the T cell synapse from single molecule techniques.''; Nat Rev Immunol, 2011 PubMed Europe PMC
  4. Sadreddini S, Baradaran B, Aghebati-Maleki A, Shanehbandi D, Fotouhi A, Aghebati-Maleki L; ''Immune checkpoint blockade opens a new way to cancer immunotherapy.''; J Cell Physiol, 2019 PubMed Europe PMC
  5. Walker LS, Sansom DM; ''The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses.''; Nat Rev Immunol, 2011 PubMed Europe PMC
  6. Ariyan CE, Brady MS, Siegelbaum RH, Hu J, Bello DM, Rand J, Fisher C, Lefkowitz RA, Panageas KS, Pulitzer M, Vignali M, Emerson R, Tipton C, Robins H, Merghoub T, Yuan J, Jungbluth A, Blando J, Sharma P, Rudensky AY, Wolchok JD, Allison JP; ''Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade.''; Cancer Immunol Res, 2018 PubMed Europe PMC
  7. Trinca C, Bressler R, Walson P; ''The drug surveillance program at the Arizona Medical Center.''; Ariz Med, 1975 PubMed Europe PMC
  8. Podojil JR, Miller SD; ''Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy.''; Immunol Rev, 2009 PubMed Europe PMC


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108125view10:27, 29 November 2019FehrhartOntology Term : 'cancer pathway' added !
104340view22:19, 17 May 2019KhanspersModified description
104339view22:15, 17 May 2019Khanspersupdated details
104107view19:21, 3 May 2019KhanspersModified description
104106view19:17, 3 May 2019KhanspersModified description
104105view18:55, 3 May 2019KhanspersOntology Term : 'adaptive immune response pathway' added !
104104view18:54, 3 May 2019KhanspersOntology Term : 'T cell' added !
104103view18:54, 3 May 2019Khanspersdecreased board size
104086view21:28, 2 May 2019KhanspersModified description
104085view21:23, 2 May 2019KhanspersOntology Term : 'professional antigen presenting cell' added !
104084view21:20, 2 May 2019KhanspersOntology Term : 'immune response pathway' added !
104083view21:20, 2 May 2019KhanspersOntology Term : 'cancer' added !
104082view21:18, 2 May 2019KhanspersNew pathway

External references


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NameTypeDatabase referenceComment
Akt SignalingPathwayWP4172 (WikiPathways)
CD28GeneProductENSG00000178562 (Ensembl)
CD80GeneProductENSG00000121594 (Ensembl)
CD86GeneProductENSG00000114013 (Ensembl)
CTLA4GeneProductENSG00000163599 (Ensembl)
IpilimumabMetaboliteQ2459042 (Wikidata)
MHC IIProteinD7RIH8 (Uniprot-TrEMBL)
PIK3CAGeneProductENSG00000121879 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18706
PIK3CBGeneProductENSG00000051382 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:74769
PIK3CDGeneProductENSG00000171608 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18707
PIK3R1GeneProductENSG00000145675 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18708
PIK3R2GeneProductENSG00000105647 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18709
PIK3R3GeneProductENSG00000117461 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:75669
PPP2CAGeneProductENSG00000113575 (Ensembl)
PTPN11GeneProductENSG00000179295 (Ensembl)
PTPN6GeneProductENSG00000111679 (Ensembl)
TCR SignalingPathwayWP69 (WikiPathways)
TRAGeneProduct6955 (Entrez Gene)
TRBGeneProduct6957 (Entrez Gene)
TremelimumabMetaboliteQ7838098 (Wikidata)
Tumor-associated antigenGeneProduct

Annotated Interactions

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