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Neutrophils as potential therapeutic targets in hepatocellular carcinoma

Abstract

The success of atezolizumab plus bevacizumab treatment contributed to a shift in systemic therapies for hepatocellular carcinoma (HCC) towards combinations that include cancer immunotherapeutic agents. Thus far, the principal focus of cancer immunotherapy has been on interrupting immune checkpoints that suppress antitumour lymphocytes. As well as lymphocytes, the HCC environment includes numerous other immune cell types, among which neutrophils are emerging as an important contributor to the pathogenesis of HCC. A growing body of evidence supports neutrophils as key mediators of the immunosuppressive environment in which some cancers develop, as well as drivers of tumour progression. If neutrophils have a similar role in HCC, approaches that target or manipulate neutrophils might have therapeutic benefits, potentially including sensitization of tumours to conventional immunotherapy. Several neutrophil-directed therapies for patients with HCC (and other cancers) are now entering clinical trials. This Review outlines the evidence in support of neutrophils as drivers of HCC and details their mechanistic roles in development, progression and metastasis, highlighting the reasons that neutrophils are well worth investigating despite the challenges associated with studying them. Neutrophil-modulating anticancer therapies entering clinical trials are also summarized.

Key points

  • A growing body of evidence identifies neutrophils as central to the pathogenesis of hepatocellular carcinoma (HCC) and as having important roles in tumorigenesis, local tumour progression and metastasis.

  • The main mechanisms by which neutrophils drive tumour progression are immunosuppression, direct enhancement of tumour cell survival, invasiveness and metastatic capacity, extracellular matrix remodelling and angiogenesis.

  • Single-cell technologies show that neutrophils probably have a dynamic spectrum of pro-tumour and antitumour functions that vary according to their microenvironment; as such, the current phenotypic classification should be revisited.

  • Preclinical studies demonstrate that targeting neutrophils is an effective strategy in HCC: therapies that selectively target tumour-promoting neutrophil functions, signalling pathways and chemotaxis are currently under investigation.

  • Manipulation of neutrophil function could potentially render the HCC immune microenvironment more permissive to systemic immunotherapies.

  • Further work, including improvements in preclinical models and single-cell technologies, is needed to determine the phenotypes of neutrophils in HCC and in chronic liver diseases.

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Fig. 1: Neutrophil tumour recruitment and polarization in hepatocellular carcinoma.
Fig. 2: Neutrophil-driven tumour-promoting mechanisms in hepatocellular carcinoma.
Fig. 3: Promising neutrophil-directed therapeutic targets in hepatocellular carcinoma.

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Acknowledgements

D.G. is funded by the Newcastle Cancer Research UK (CRUK) Clinical Academic Training Programme. T.G.B. is funded by the Wellcome Trust (grant WT107492Z). D.A.M. received grant funding from the UK Medical Research Council (MRC) (grants MR/K0019494/1 and MR/R023026/1). J.L., D.A.M. and H.L.R. received grant funding from CRUK (grant C18342/A23390). T.G.B., D.A.M. and H.L.R. received funding from the CRUK Hepatocellular Carcinoma Expediter Network (HUNTER) Accelerator Award (A26813).

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D.G., T.G.B., and D.A.M. contributed to all aspects of the article. J.L. and H.L.R. contributed substantially to discussions of the content, writing and review or editing of the manuscript before submission. R.R. researched data for the article and wrote the manuscript.

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Correspondence to Derek A. Mann.

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Nature Reviews Gastroenterology & Hepatology thanks Allan Tsung, who co-reviewed with Hai Huang; Tim Greten; and Limin Zheng for their contribution to the peer review of this work.

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Glossary

Neutrophil extracellular traps

(NETs). Extracellular web-like structures released by activated neutrophils, made up of a network of chromatin and granule proteins such as neutrophil elastase and myeloperoxidase; NETs have a variety of antimicrobial and immune-modulating functions.

Tumour-associated neutrophils

(TANs). The neutrophils found within or around a tumour.

Reactive oxygen species

(ROS). Unstable molecules containing oxygen free radicals (such as hydrogen peroxide and superoxides) that readily react with other molecules; stimulated neutrophils generate ROS by activating the NADPH oxidase complex, which is one of their main antimicrobial mechanisms.

Stelic animal model

(STAM). In STAM mice, hepatocellular carcinoma (HCC) develops on the background of streptozotocin-induced type 1 diabetes mellitus and steatosis induced by a high-fat diet, which mimics the development of HCC on the background of nonalcoholic steatohepatitis.

Trogoptosis

A mechanism by which neutrophils exert antibody-dependent cellular cytotoxicity (ADCC) towards tumour cells; trogoptosis is restricted by CD47–SIRPα interactions and involves trogocytosis, which activates neutrophil degranulation and cytotoxicity.

Heterotopic model

The implantation of tumour cells into organs or tissues of an animal that do not match the tumour cells’ organ or tissues of origin.

Orthotopic model

The implantation of tumour cells into the organ or tissues of an animal that match the tumour cells organ or tissues of origin.

Syngeneic

Cells with an identical genetic background, which are immunologically compatible and therefore can be transplanted into another organism without eliciting an immune response.

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Geh, D., Leslie, J., Rumney, R. et al. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 19, 257–273 (2022). https://doi.org/10.1038/s41575-021-00568-5

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