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Context-dependent functions of pattern recognition receptors in cancer

Nature Reviews Cancer volume 22, pages 397–413 (2022)Cite this article

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Abstract

The immune system plays a critical role in shaping all facets of cancer, from the early initiation stage through to metastatic disease and resistance to therapy. Our understanding of the importance of the adaptive arm of the immune system in antitumour immunity has led to the implementation of immunotherapy with immune checkpoint inhibitors in numerous cancers, albeit with differing efficacy. By contrast, the clinical utility of innate immunity in cancer has not been exploited, despite dysregulated innate immunity being a feature of at least one-third of all cancers associated with tumour-promoting chronic inflammation. The past two decades have seen innate immune pattern recognition receptors (PRRs) emerge as critical regulators of the immune response to microbial infection and host tissue damage. More recently, it has become apparent that in many cancer types, PRRs play a central role in modulating a vast array of tumour-inhibiting and tumour-promoting cellular responses both in immune cells within the tumour microenvironment and directly in cancer cells. Herein, we provide a comprehensive overview of the fast-evolving field of PRRs in cancer, and discuss the potential to target PRRs for drug development and biomarker discovery in a wide range of oncology settings.

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Fig. 1: Pattern recognition receptors orchestrate diverse cellular processes relevant to cancer development and progression.
Fig. 2: Pattern recognition receptors induce tumour-promoting activities in immune cells.
Fig. 3: Pattern recognition receptors induce tumour-inhibitory activities in immune cells.
Fig. 4: Pattern recognition receptors induce tumour-promoting activities in non-immune cells.
Fig. 5: Pattern recognition receptors induce tumour-inhibitory activities in non-immune cells.

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Acknowledgements

The authors thank R. Smith (Hudson Institute of Medical Research, Melbourne, Australia) for editing the manuscript. B.J.J. is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia. S.M.M. is supported by a CSL Centenary Fellowship.

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Authors and Affiliations

  1. Division of Immunity, Inflammation and Infection, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia

    Si Ming Man

  2. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia

    Brendan J. Jenkins

  3. Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, Australia

    Brendan J. Jenkins

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Glossary

Pattern recognition receptors

(PRRs). Protein receptors expressed on the cell surface or in intracellular compartments (cytosol, nucleus and endosomes) of immune and non-immune cells. They recognize conserved molecular structures in microorganisms (pathogen-associated molecular patterns) or host-derived molecules released by damaged or dying cells (damage-associated molecular patterns).

MyD88

Myeloid differentiation primary response protein 88, a key signalling adaptor protein of members of the Toll-like receptor (TLR) (except TLR3) and IL-1 receptor families.

NLRP3

Nucleotide-binding oligomerization domain (NOD), leucin-rich repeat and pyrin domain-containing 3 (NLRP3), the best characterized pattern recognition receptor protein among the NLRP subfamily of NOD-like receptors for its role in pyroptosis (programmed inflammatory cell death) and inflammation.

Inflammasome

A multiprotein signalling hub comprising absent in melanoma 2 (AIM2), pyrin or nucleotide-binding oligomerization domain-like receptors (NLRC4/NAIP, NLRP1B, NLRP3, NLRP6 and NLRP12) as a sensor, the adaptor protein ASC and the cysteine protease caspase 1, which controls the production of mature, biologically active cytokines IL-1β and IL-18.

cGAS–STING

Cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS) is a cytosolic sensor of microbial (viral) and host (nuclear or mitochondrial) DNA, and activates its downstream effector protein stimulator of interferon genes (STING) in immune and non-immune (for example, epithelial cancer) cells to facilitate innate and adaptive immune responses.

Chemical carcinogen

A genotoxic chemical used in mouse models to elicit carcinogenesis in specific tissues, such as azoxymethane in colorectal cancer, 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol 13-acetate in skin cancer and diethylnitrosamine in liver cancer. Azoxymethane used with dextran sodium sulfate also induces colitis-associated colorectal cancer.

M2 macrophages

Protumorigenic (alternatively activated) macrophages with activities including production of anti-inflammatory cytokines that create an immunosuppressive tumour microenvironment.

TRIF

TIR domain-containing adaptor protein inducing interferon-β (IFNβ), an adaptor protein of Toll-like receptor 3 (TLR3) and TLR4 that contributes to inducing the production of type I interferons.

M1 macrophage

Classically activated macrophage with antitumour functions, including microbicidal activity and facilitating a T helper 1-type response while simultaneously dampening T helper 2-type responses.

Type I interferon

Polypeptides (for example, interferon-α (IFNα) and IFNβ) secreted by immune and non-immune (for example, tumour) cells that have several functions, including antimicrobial responses, promotion of antigen presentation by innate immune cells and activation of adaptive immunity, incorporating T cell-mediated antitumour immunity.

Senescence-associated secretory phenotype

A network of secreted factors produced by senescent cells, including cytokines, chemokines, growth factors, secreted proteases and non-protein metabolites.

Hypoxia-inducible factor 1α

An evolutionarily conserved transcription factor whose expression increases during hypoxia (low-oxygen condition) and can induce the expression of genes supporting multiple cellular processes, such as cell proliferation, survival and glucose metabolism.

Bacillus Calmette–Guérin

(BCG). Named after its inventors Albert Calmette and Camille Guérin, a live attenuated strain of Mycobacterium bovis comprising Toll-like receptor 2 (TLR2)/TLR4-activating components (for example, peptidoglycans) that is used primarily as a vaccine against tuberculosis.

MCC950

Small-molecule chemical inhibitor (also known as CP-456,773 or CRID3) of NLRP3 that directly binds to the NLRP3 NACHT domain and blocks ATP hydrolysis, inhibiting NLRP3 inflammasome activation.

Canakinumab Anti-inflammatory Thrombosis Outcome Study

(CANTOS). A large, randomized, double-blind trial involving the administration of the IL-1β-blocking antibody canakinumab to patients with atherosclerosis.

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Man, S.M., Jenkins, B.J. Context-dependent functions of pattern recognition receptors in cancer. Nat Rev Cancer 22, 397–413 (2022). https://doi.org/10.1038/s41568-022-00462-5

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