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  • Review Article
  • Published:

Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors

Nature Reviews Cancer volume 6, pages 613–625 (2006)Cite this article

An Erratum to this article was published on 17 August 2006

Key Points

  • Tumours dominantly suppress anti-tumour immunity through various pro-toleragenic mechanisms. A particularly attractive approach to target these mechanisms might be through the development of small-molecule immunotherapeutic drugs.

  • The indoleamine 2,3-dioxygenase (IDO) enzyme, which catabolizes the essential amino acid tryptophan, promotes tumoral immune tolerance by blocking the activation of effector T cells. Cancer cells express IDO, as do antigen-presenting dendritic cells that are present in tumour-draining lymph nodes, and both might contribute to immune escape. A small-molecule IDO inhibitor is in preclinical development.

  • The arginase (ARG)1 enzyme, which is expressed by tumour cells, myeloid suppressor cells and tumour-associated macrophages, has been implicated in suppressing anti-tumour immunity through catabolism of the amino acid arginine. Inducible nitric-oxide synthase (iNOS), another enzyme that catabolizes arginine, generally shows reciprocal regulation to ARG. However, in the context of some tumours, increased expression of both enzymes might contribute to immune suppression. Nitroaspirin, which inhibits both enzymes, is currently the most promising small molecule in development.

  • The cyclooxygenase 2 (COX2) enzyme has a central role in regulating the mechanisms of immune suppression and promotes the generation of regulatory T cells. Selective COX2 inhibitors have demonstrated evidence of additional clinical benefit in combination with chemotherapeutic agents, but recent concerns over safety have slowed testing. Inhibitors that target the prostaglandin receptors might represent an alternative.

  • The transforming growth factor β (TGFβ) cytokine can have profound immunosuppressive effects, and cancer cells adapt by becoming refractory to TGFβ signalling. Several approaches aimed at inhibiting TGFβ signalling are currently being investigated in terms of therapeutic potential, including small-molecule inhibitors of the TGFβ receptor tyrosine kinase.

  • Targeting downstream Janus kinase (JAK)–signal-tansducer-and-activator-of-transcription (STAT) signalling pathways might be an option for interfering with toleragenic cytokine activity, as might the vascular-endothelial-growth-factor (VEGF) receptor FMS-related tyrosine kinase 1 (FLT1), which can promote defective dendritic-cell maturation. Chemokines have also been implicated in the recruitment of immunosuppressive effector cell types to the local tumour microenvironment. Small-molecule inhibitors of the chemokine receptors CCR4, CXCR4 and CCR2 are currently in preclinical development.

  • One potential application of anti-toleragenic, small-molecule immunotherapeutics might be in combination with standard cytotoxic chemotherapies. The possibility that these new agents might improve standard treatments should facilitate clinical testing.

Abstract

Cancer immunotherapy has been predominantly focused on biologically based intervention strategies. However, recent advances in the understanding of tumour–host interactions at the molecular level have revealed targets that might be amenable to intervention with small-molecule inhibitors. In particular, key effectors of tumoral immune escape have been identified that contribute to a dominant toleragenic state that is suspected of limiting the successful implementation of treatment strategies that rely on boosting immune function. Within the context of the pathophysiology of cancer-associated immune tolerance, this Review delineates potential molecular targets for therapeutic intervention and the progress that has been made in developing small-molecule inhibitors.

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Figure 1: Interactions between the tumour and cells of the immune system that foster an immunosuppressive microenvironment.
Figure 2: Inter-regulation of the various cytokines and enzymes associated with immune suppression.

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Acknowledgements

A.J.M. receives support through the Department of Defense Breast Cancer Research Program, the State of Pennsylvania Department of Health (CURE/Tobacco Settlement Award), the Lance Armstrong Foundation and the Concern Foundation.

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Authors and Affiliations

  1. Lankenau Institute for Medical Research, Wynnewood, 19096, Pennsylvania, USA

    Alexander J. Muller

  2. Incyte Corporation, Wilmington, 19880, Delaware, USA

    Peggy A. Scherle

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Correspondence to Alexander J. Muller.

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DATABASES

National Cancer Institute

colorectal cancer

NSCLC

ovarian cancer

pancreatic cancer

prostate cancer

RCC

skin cancer

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Glossary

Toleragenic state

A state of immune-system unresponsiveness that is actively promoted by tumour cells to avoid immune recognition.

Antigen-presenting cells

(APCs). Cells that process antigen and present antigen fragments to other cells of the immune system (cross-presentation) to initiate an immune response. Dendritic cells are the most potent APCs.

M1 macrophage

A macrophage subtype that produces pro-inflammatory cytokines and acts as an effector of cell killing.

M2 macrophage

A macrophage subtype that acts to dampen inflammatory responses and scavenge debris, as well as promote angiogenesis and tissue remodelling and repair.

Mixed lymphocyte reaction

(MLR). An in vitro assay designed to measure the T-cell proliferation that occurs in response to cells bearing allogeneic MHC class I and class II molecules. Used to assess T-cell functional capacity.

Plasmacytoid morphology

There are two main subsets of dendritic cell in the human system; myeloid and plasmacytoid. Plasmacytoid dendritic cells look like plasma cells (antibody-producing B cells), and can produce high amounts of interferon-α.

Autochthonous

Originating where found. Distinguishes mouse cancer models bearing de novo-formed tumours from more commonly used tumour-cell graft models.

Severe combined immunodeficient mice

SCID mice are homozygous for the spontaneous Prkdcscid mutation in the protein kinase, DNA-activated, catalytic polypeptide encoding gene. These mice are characterized by an absence of functional T cells and B cells and are excellent hosts for allografts and xenografts.

TH2 responses

A T-helper-2 response involves production of cytokines, such as IL4, which stimulate antibody production. TH2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens as well as allergic reactions.

TH1 responses

A T-helper-1 cell-mediated immune response is mediated by pro-inflammatory cytokines such as IFNγ, IL1 and TNFα. It promotes cellular immune responses against intracellular infections and malignancy.

Cytotoxic T lymphocyte-associated antigen-4

CTLA4 is a co-stimulatory-type molecule that antagonizes effector-T-cell responses.

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Muller, A., Scherle, P. Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat Rev Cancer 6, 613–625 (2006). https://doi.org/10.1038/nrc1929

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