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Editorial
. 2014 Dec 4;371(23):2230-2.
doi: 10.1056/NEJMe1413061. Epub 2014 Nov 19.

Somatic mutations and immunotherapy outcome with CTLA-4 blockade in melanoma

Vassiliki A Boussiotis  1
Affiliations
Editorial

Somatic mutations and immunotherapy outcome with CTLA-4 blockade in melanoma

Vassiliki A Boussiotis. N Engl J Med. .
No abstract available

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Figures

Figure 1
Figure 1. Somatic Neoepitopes of Melanomas and Benefit from CTLA-4 Blockade
Recognition of epitopes by T-cell receptors can be mediated by consensus tetrapeptides in immunogenic peptides. As shown in Panel A, mutant tetrapeptides that bind major histocompatibility complex (MHC) class I molecules with high affinity induce activation of antigen-specific naive or memory T cells that recognize this tumor-specific antigen, leading to translocation of cytotoxic T-lymphocyte antigen 4 (CTLA-4)–containing vesicles to the immunologic synapse and up-regulation of CTLA-4 expression on the cell surface. Ligation of CTLA-4 by B7-1 and B7-2 mediates an inhibitory signal in these tumor-specific T cells. Under these conditions, anti–CTLA-4 antibodies prevent CTLA-4 ligation and CTLA-4–mediated inhibition, resulting in the generation of functional tumor-specific effector T cells, which induce anti-tumor responses. As shown in Panel B, in the absence of such mutations, nonmutant tetrapeptides corresponding to the nonmutated counterparts of immunogenic somatic neoepitopes have lower affinity for MHC class I molecules and do not induce activation of antigen-specific naive or memory T cells that recognize this tumor-specific antigen. Under these conditions, CTLA-4–containing vesicles do not translocate to the immunologic synapse, CTLA-4 expression is not up-regulated, and anti–CTLA-4 antibodies confer no clinical benefit.
See this image and copyright information in PMC

Comment on

  • Genetic basis for clinical response to CTLA-4 blockade in melanoma.
    Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA. Snyder A, et al. N Engl J Med. 2014 Dec 4;371(23):2189-2199. doi: 10.1056/NEJMoa1406498. Epub 2014 Nov 19. N Engl J Med. 2014. PMID: 25409260 Free PMC article.

References

    1. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–1558. - PMC - PubMed
    1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non�small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–2139. - PubMed
    1. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516. - PMC - PubMed
    1. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non�small-cell lung cancer. N Engl J Med. 2010;363:1693–1703. [Erratum, N Engl J Med 2011;364:588.] - PMC - PubMed
    1. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–421. - PMC - PubMed