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  • Review Article
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The blockade of immune checkpoints in cancer immunotherapy

Nature Reviews Cancer volume 12, pages 252–264 (2012)Cite this article

Subjects

Key Points

  • The huge number of genetic and epigenetic changes that are inherent to most cancer cells provide plenty of tumour-associated antigens that the host immune system can recognize, thereby requiring tumours to develop specific immune resistance mechanisms. An important immune resistance mechanism involves immune-inhibitory pathways, termed immune checkpoints, which normally mediate immune tolerance and mitigate collateral tissue damage.

  • A particularly important immune-checkpoint receptor is cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), which downmodulates the amplitude of T cell activation. Antibody blockade of CTLA4 in mouse models of cancer induced antitumour immunity.

  • Clinical studies using antagonistic CTLA4 antibodies demonstrated activity in melanoma. Despite a high frequency of immune-related toxicity, this therapy enhanced survival in two randomized Phase III trials. Anti-CTLA4 therapy was the first agent to demonstrate a survival benefit in patients with advanced melanoma and was approved by the US Food and Drug Administration (FDA) in 2010.

  • Some immune-checkpoint receptors, such as programmed cell death protein 1 (PD1), limit T cell effector functions within tissues. By upregulating ligands for PD1, tumour cells block antitumour immune responses in the tumour microenvironment.

  • Early-stage clinical trials suggest that blockade of the PD1 pathway induces sustained tumour regression in various tumour types. Responses to PD1 blockade may correlate with the expression of PD1 ligands by tumour cells.

  • Multiple additional immune-checkpoint receptors and ligands, some of which are selectively upregulated in various types of tumour cells, are prime targets for blockade, particularly in combination with approaches that enhance the activation of antitumour immune responses, such as vaccines.

Abstract

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand–receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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Figure 1: Multiple co-stimulatory and inhibitory interactions regulate T cell responses.
Figure 2: Clinical responses and immune-mediated toxicities on antibody blockade of the CTLA4-mediated immune checkpoint.
Figure 3: Immune checkpoints regulate different components in the evolution of an immune response.
Figure 4: Two general mechanisms of expression of immune-checkpoint ligands on tumour cells.
Figure 5: Implications of the adaptive immune resistance mechanism for combinatorial immunotherapy of cancer.

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Acknowledgements

Work in the author's laboratory is supported by the Melanoma Research Alliance, the Hussman Foundation and the Seraph Foundation.

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  1. Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, CRB1 Room 444, 1650 Orleans Street, Baltimore, 21287, Maryland, USA

    Drew M. Pardoll

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Glossary

Amplitude

In immunology, this refers to the level of effector output. For T cells, this can be levels of cytokine production, proliferation or target killing potential.

Quality

In immunology, this refers to the type of immune response generated, which is often defined as the pattern of cytokine production. This, in turn, mediates responses against specific types of pathogen. For example, CD4+ T cells can be predominantly: TH1 cells (characterized by IFNγ production; these cells are important for antiviral and antitumour responses); TH2 cells (characterized by IL-4 and IL-13 production; these cells are important for antihelminth responses); or TH17 cells (characterized by IL-17 and IL-22 production; these cells are important for mucosal bacterial and fungal responses).

Autoimmunity

Immune responses against an individual's normal cells or tissues.

CD8+ effector T cells

T cells that are characterized by the expression of CD8. They recognize antigenic peptides presented by MHC class I molecules and are able to directly kill target cells that express the cognate antigen.

CD4+ helper T cells

T cells that are characterized by the expression of CD4. They recognize antigenic peptides presented by MHC class II molecules. This type of T cell produces a vast range of cytokines that mediate inflammatory and effector immune responses. They also facilitate the activation of CD8+ T cells and B cells for antibody production.

Myeloid cells

Any white blood cell (leukocyte) that is not a lymphocyte: macrophages, dendritic cells and granulocytic cells.

Suicide substrates

Molecules that inhibit an enzyme by mimicking its substrate and covalently binding to the active site.

Antigen-presenting cell

(APC). Any cell that displays on its surface an MHC molecule with a bound peptide antigen that a T cell recognizes through its TCR. This can be a dendritic cell or a macrophage, or any cell that expresses antigen and would be killed by an activated CD8+ effector T cell-specific response (such as a tumour cell or virally infected cell).

Regulatory T (TReg) cell

A type of CD4+ T cell that inhibits, rather than promotes, immune responses. They are characterized by the expression of the forkhead transcription factor FOXP3, the lack of expression of effector cytokines such as IFNγ and the production of inhibitory cytokines such as TGFβ, IL-10 and IL-35.

Immunogenic tumours

In the case of tumours in mice, this refers to a tumour that naturally elicits an immune response when growing in a mouse. With regard to human tumours, melanoma is typically considered immunogenic because patients with melanoma often have increased numbers of T cells that are specific for melanoma antigens.

Objective clinical responses

A diminution of total cross-sectional area of all metastatic tumours — as measured by a CT or MRI scan — by >30% (corresponding to ∼50% decrease in volume) with no growth of any metastatic tumours.

Response rate

The proportion of treated patients that achieve an objective response.

Natural killer (NK) cells

Immune cells that kill cells using mechanisms similar to CD8+ effector T cells but do not use a clonal TCR for recognition. Instead, they are activated by receptors for stress proteins and are inhibited through distinct receptors, many of which recognize MHC molecules independently of the bound peptide.

Anergy

A form of T or B cell inactivation in which the cell remains alive but cannot be activated to execute an immune response. Anergy is a reversible state.

Mixed response

Response to a therapy whereby some metastatic tumours shrink and others grow.

Partial response

An objective response in which some tumours remain visible on CT or MRI scans.

Complete response

An objective response in which all measurable tumours completely disappear.

Macrophages

Specialized immune cells that, on stimulation by pathogen-derived molecules or T cells, will engulf pathogens (particularly those that have antibodies or complement bound to them). They can also present antigen to T cells, but not as efficiently as dendritic cells.

Dendritic cells

Specialized immune cells that, when activated, present antigens to and activate T cells to initiate adaptive immune responses.

Graft-versus-tumour effects

An immune attack against tumour cells in the host mediated by transplanted allogeneic T cells.

Allogeneic

Cells from a different individual that express different MHC alleles.

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Pardoll, D. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12, 252–264 (2012). https://doi.org/10.1038/nrc3239

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