CD278 explained

Inducible T-cell costimulator (also called CD278) is an immune checkpoint protein that in humans is encoded by the ICOS (Inducible T-cell COStimulator) gene.[1] [2] [3] [4] [5] The protein belongs to the CD28 and CTLA-4 cell-surface receptor family. These are proteins expressed on the surface of immune cells that mediate signalling between them. A surface protein, the ligand, binds specifically to its receptor on another cell, leading to a signalling cascade in that cell.

Function

ICOS is a receptor protein expressed on the surface of activated T cells. Its ligand ICOS-L (previously called B7RP-1) is constitutively expressed on B cells. Stimulation of the ICOS receptor on T cells by ICOS-L on B cells is required for the development of follicular helper T (Tfh) cells.[6] ICOS forms homodimers and plays an important role in cell-cell signaling, immune responses and regulation of cell proliferation.[3]

Knockout phenotype

Compared to wild-type naïve T cells, ICOS-/- T cells activated with plate-bound anti-CD3 have reduced proliferation and IL-2 secretion.[7] The defect in proliferation can be rescued by addition of IL-2 to the culture, suggesting the proliferative defect is due either to ICOS-mediated IL-2 secretion or the activation of similar signaling pathways between ICOS and IL-2. In terms of Th1 and Th2 cytokine secretion, ICOS-/- CD4+ T cell activated in vitro reduced IL-4 secretion, while maintaining similar IFN-g secretion. Similarly, CD4+ T cells purified from ICOS-/- mice immunized with the protein keyhole limpet hemocyanin (KLH) in alum or complete Freund's Adjuvant have attenuated IL-4 secretion, but similar IFN-g and IL-5 secretion when recalled with KLH.

These data are similar to an airway hypersensitivity model showing similar IL-5 secretion, but reduced IL-4 secretion in response to sensitization with Ova protein, indicating a defect in Th2 cytokine secretion, but not a defect in Th1 differentiation as both IL-4 and IL-5 are Th2-associated cytokines. In agreement with reduced Th2 responses, ICOS-/- mice expressed reduced germinal center formation and IgG1 and IgE antibody titers in response to immunization.

Combination therapy

Ipilimumab patients expressed increased ICOS+ T cells in tumor tissues and blood. The increase served as a pharmacodynamic biomarker of anti-CTLA-4 treatment. In wild-type C57BL/6 mice, anti-CTLA-4 treatment resulted in tumor rejection in 80 to 90% of subjects, but in gene-targeted mice that were deficient for either ICOS or its ligand (ICOSLG), the efficacy was less than 50%. An agonistic stimulus for the ICOS pathway during anti-CTLA-4 therapy resulted in an increase in efficacy that was about four to five times as large as that of control treatments. This combination therapy incorporating ICOS costimulation and CTLA-4 blockade effectively remodels tumor-associated macrophages (TAMs) towards an antitumor phenotype, demonstrating promising therapeutic potential in cancer treatment.[8] As of 2015 antibodies for ICOS were not available for clinical testing.[9]

Further reading

Notes and References

  1. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA . ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28 . Nature . 397 . 6716 . 263–6 . Jan 1999 . 9930702 . 10.1038/16717 . 1999Natur.397..263H . 4415254 .
  2. Yoshinaga SK, Whoriskey JS, Khare SD, Sarmiento U, Guo J, Horan T, Shih G, Zhang M, Coccia MA, Kohno T, Tafuri-Bladt A, Brankow D, Campbell P, Chang D, Chiu L, Dai T, Duncan G, Elliott GS, Hui A, McCabe SM, Scully S, Shahinian A, Shaklee CL, Van G, Mak TW, Senaldi G . T-cell co-stimulation through B7RP-1 and ICOS . Nature . 402 . 6763 . 827–32 . Dec 1999 . 10617205 . 10.1038/45582 . 1999Natur.402..827Y . 4360410 .
  3. Web site: Entrez Gene: ICOS inducible T-cell co-stimulator.
  4. Rudd CE, Schneider H . Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling . Nature Reviews. Immunology . 3 . 7 . 544–56 . Jul 2003 . 12876557 . 10.1038/nri1131 . 19833513 .
  5. Dong C, Juedes AE, Temann UA, Shresta S, Allison JP, Ruddle NH, Flavell RA . ICOS co-stimulatory receptor is essential for T-cell activation and function . Nature . 409 . 6816 . 97–101 . Jan 2001 . 11343121 . 10.1038/35051100 . 2001Natur.409...97D . 11891841 .
  6. Akiba . Hisaya . The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo . The Journal of Immunology . 2005 . 175 . 4 . 2340–2348 . 10.4049/jimmunol.175.4.2340 . 16081804 .
  7. Book: Stefan . Dübel . Janice M. . Reichert. Handbook of Therapeutic Antibodies . 2014 . Wiley-VCH . Weinheim, Bergstr . 978-3-527-32937-3 . 1088–9 . 2 . https://books.google.com/books?id=I9k8BAAAQBAJ&q=ICOS+IL-2+CD3++Th1+Th2&pg=PA1088 . Frank R. . Brennan . T Cell Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders .
  8. Sharma N, Fan X, Atolagbe OT, Ge Z, Dao KN, Sharma P, Allison JP . ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype. The Journal of Experimental Medicine . 221 . 4 . April 2024 . 38517331 . 10959121 . 10.1084/jem.20231263 .
  9. Sharma P, Allison JP . The future of immune checkpoint therapy . Science . 348 . 6230 . 56–61 . Apr 2015 . 25838373 . 10.1126/science.aaa8172 . 2015Sci...348...56S . 4608450 .

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