Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jun 10;33(17):1974-82.
doi: 10.1200/JCO.2014.59.4358. Epub 2015 Jan 20.

Immune Checkpoint Blockade in Cancer Therapy

Michael A Postow  1 , Margaret K Callahan  1 , Jedd D Wolchok  2
Affiliations
Review

Immune Checkpoint Blockade in Cancer Therapy

Michael A Postow et al. J Clin Oncol. .

Abstract

Immunologic checkpoint blockade with antibodies that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have demonstrated promise in a variety of malignancies. Ipilimumab (CTLA-4) and pembrolizumab (PD-1) are approved by the US Food and Drug Administration for the treatment of advanced melanoma, and additional regulatory approvals are expected across the oncologic spectrum for a variety of other agents that target these pathways. Treatment with both CTLA-4 and PD-1/PD-L1 blockade is associated with a unique pattern of adverse events called immune-related adverse events, and occasionally, unusual kinetics of tumor response are seen. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade are being investigated to determine whether they enhance the efficacy of either approach alone. Principles learned during the development of CTLA-4 and PD-1/PD-L1 approaches will likely be used as new immunologic checkpoint blocking antibodies begin clinical investigation.

PubMed Disclaimer

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
The cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) immunologic checkpoint. T-cell activation requires antigen presentation in the context of a major histocompatibility complex (MHC) molecule in addition to the costimulatory signal achieved when B7 on an antigen-presenting cell (dendritic cell shown) interacts with CD28 on a T cell. Early after activation, to maintain immunologic homeostasis, CTLA-4 is translocated to the plasma membrane where it downregulates the function of T cells.
Fig 2.
Fig 2.
The programmed cell death protein 1 (PD-1) immunologic checkpoint. PD-1 is expressed on activated T cells. Interactions between PD-1 and its ligands, PD-L1 and PD-L2, are complex and occur at multiple steps of an immune response. For illustration, we have shown an interaction early after activation in the lymph node where PD-L1/PD-L2 on an antigen-presenting cell (dendritic cell shown) negatively regulates T-cell activity through PD-1 and through an interaction between B7 and PD-L1. The PD-1 pathway is also likely important in the tumor microenvironment where PD-L1 expressed by tumors interacts with PD-1 on T cells to suppress T-cell effector function. MHC, major histocompatibility complex.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Linsley PS, Brady W, Urnes M, et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:561–569. - PMC - PubMed
    1. Schneider H, Downey J, Smith A, et al. Reversal of the TCR stop signal by CTLA-4. Science. 2006;313:1972–1975. - PubMed
    1. Riley JL, Mao M, Kobayashi S, et al. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc Natl Acad Sci USA. 2002;99:11790–11795. - PMC - PubMed
    1. Qureshi OS, Zheng Y, Nakamura K, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332:600–603. - PMC - PubMed
    1. Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med. 1996;183:2533–2540. - PMC - PubMed

MeSH terms

-