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 Apr 13;27(4):450-61.
doi: 10.1016/j.ccell.2015.03.001. Epub 2015 Apr 6.

Immune checkpoint blockade: a common denominator approach to cancer therapy

Suzanne L Topalian  1 , Charles G Drake  2 , Drew M Pardoll  3
Affiliations
Review

Immune checkpoint blockade: a common denominator approach to cancer therapy

Suzanne L Topalian et al. Cancer Cell. .

Abstract

The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during anti-microbial immune responses, can be co-opted by cancer to evade immune destruction. Drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions. The complex biology of immune checkpoint pathways still contains many mysteries, and the full activity spectrum of checkpoint-blocking drugs, used alone or in combination, is currently the subject of intense study.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Complex interactions between the CTLA-4/CD28 and PD-1 families of receptors and ligands
Shown are the defined interactions between the co-inhibitory (checkpoint) receptors, CTLA-4 and PD-1, and their ligands and related receptors. The two known ligands for CTLA-4 are CD80 (B7.1) and CD86 (B7.2). CD86 can “backwards signal” into antigen presenting cells (APCs) when engaged by CTLA-4, inducing the immune inhibitory enzyme indolamine 2’3’ dioxygenase (IDO). CD80 and CD86 also bind the co-stimulatory receptor CD28 on T cells. Recently, another B7 family member, ICOS-L, which was discovered as the ligand for the co-stimulatory receptor ICOS (not shown), was reported to bind to CD28 leading to co-stimulation independent of CD80 or CD86. The two defined ligands for PD-1, namely PD-L1 (B7-H1) and PD-L2 (B7-DC), bind to additional molecules. PD-L1 binds CD80 molecules expressed on activated T cells, mediating inhibition. Additionally, PD-L1 on APCs appears to provide inhibitory signals (“backwards signaling”) when it is engaged by PD-1. PD-L2 binds another molecule, repulsive guidance molecule b (RGMb), which is expressed on macrophages and some epithelial cell types and appears to deliver an inhibitory immune signal through an as yet undefined mechanism. Though not identified, genetic evidence from PD-1 knockout T cells and knockout mice suggests the existence of another receptor for PD-L2 that is co-stimulatory.
Figure 2
Figure 2. Two general mechanisms for expression of checkpoint ligands in the tumor microenvironment (TME)
The examples in this figure use the PD-1 ligand, PD-L1 for illustrative purposes although the concept likely applies to multiple checkpoint ligands. Top: Innate immune resistance. In some tumors, constitutive oncogenic signaling, such as through activation of the AKT pathway or gene amplification, can up-regulate PD-L1 expression on tumor cells independently of inflammatory signals in the TME. Bottom: Adaptive immune resistance refers to PD-L1 induction in tumors as an adaptation to sensing of immune attack. In adaptive resistance, PD-L1 is not constitutively expressed but rather, is induced by inflammatory signals such as IFN-g produced by T cells attempting to execute an active anti-tumor response. Expression of PD-L1 in a non-uniform distribution associated with lymphocyte infiltrates suggests adaptive induction in response to immune reactivity within the TME. Adaptive resistance can be generated by cytokine-induced PD-L1 expression on either tumor cells themselves or on leukocytes (macrophages, myeloid suppressor cells, dendritic cells or even lymphocytes) in the TME. Inhibition of tumor specific T cells by PD-L1- (or PD-L2)-expressing leukocytes may involve cross-presentation of tumor antigens such that PD-1-dependent inhibition is in cis. Adaptive resistance may be a common mechanism for the intratumoral expression of multiple immune checkpoint molecules.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114:1537–1544. - PMC - PubMed
    1. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J. Med. 2014 - PMC - PubMed
    1. Baitsch L, Legat A, Barba L, Fuertes Marraco SA, Rivals JP, Baumgaertner P, Christiansen-Jucht C, Bouzourene H, Rimoldi D, et al. Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation, antigen-specificity and anatomical localization. PLoS One. 2012;7:e30852. - PMC - PubMed
    1. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–687. - PubMed
    1. Benson DM, Jr, Caligiuri MA. Killer immunoglobulin-like receptors and tumor immunity. Cancer Immunol Res. 2014;2:99–104. - PMC - PubMed

Publication types

MeSH terms

  NODES
twitter 2