Neutrophils as potential therapeutic targets in hepatocellular carcinoma

• Published in: Nature reviews. Gastroenterology & hepatology Vol. 19; no. 4; pp. 257 - 273
• Main Authors: Geh, Daniel, Leslie, Jack, Rumney, Rob, Reeves, Helen L., Bird, Thomas G., Mann, Derek A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2022; Nature Publishing Group
• Subjects: 631/67/1059; 631/67/1504/1610/4029; 692/4020/1503/1607/1610/4029; 692/4020/4021/1607/1610/4029; 692/4028/67/1504/1610/4029; Bevacizumab; Biomedicine; Cancer immunotherapy; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Clinical trials; Gastroenterology; Hepatocellular carcinoma; Hepatology; Humans; Immune checkpoint; Immunotherapy; Leukocytes (neutrophilic); Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Lymphocytes; Lymphocytes - pathology; Medicine; Medicine & Public Health; Metastases; Metastasis; Neutrophils; Phenotypes; Review Article; Therapeutic targets; Tumorigenesis; Tumors
• DOI: 10.1038/s41575-021-00568-5
• ISSN: 1759-5045

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. Growing evidence indicates that neutrophils are involved in tumorigenesis, progression and metastasis of hepatocellular carcinoma (HCC). Here, Geh and colleagues summarize neutrophil phenotypes in HCC, describe the pathogenetic mechanisms underlying these contributions of neutrophils to HCC and highlight emerging neutrophil-targeted therapies. 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.