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Antitumour immunity regulated by aberrant ERBB family signalling

Abstract

Aberrant signalling of ERBB family members plays an important role in tumorigenesis and in the escape from antitumour immunity in multiple malignancies. Molecular-targeted agents against these signalling pathways exhibit robust clinical efficacy, but patients inevitably experience acquired resistance to these molecular-targeted therapies. Although cancer immunotherapies, including immune checkpoint inhibitors (ICIs), have shown durable antitumour response in a subset of the treated patients in multiple cancer types, clinical efficacy is limited in cancers harbouring activating gene alterations of ERBB family members. In particular, ICI treatment of patients with non-small cell lung cancers with epidermal growth factor receptor (EGFR) alterations and breast cancers with HER2 alterations failed to show clinical benefits, suggesting that EGFR and HER2 signalling may have an essential role in inhibiting antitumour immune responses. Here, we discuss the mechanisms by which the signalling of ERBB family members affects not only autonomous cancer hallmarks, such as uncontrolled cell proliferation, but also antitumour immune responses in the tumour microenvironment and the potential application of immune-genome precision medicine into immunotherapy and molecular-targeted therapy focusing on the signalling of ERBB family members.

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Fig. 1: Signalling pathways caused by ERBB family members.
Fig. 2: The effects of EGFR signalling on immune cells in the TME.
Fig. 3: Reduced antigenicity in EGFR-mutated or HER2-amplified cancer.
Fig. 4: Targeting molecular pathways of ERBB family signalling for combination immunotherapies.

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Acknowledgements

This study was supported by Grants-in-Aid for Scientific Research grant no. 17H06162 (to H.N.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Projects for Cancer Research by Therapeutic Evolution (P-CREATE; no. 16cm0106301h0001 to H.N. and no. 19cm0106335h0002 and 19cm0106310h0004 to S.Ko.), the Development of Technology for Patient Stratification Biomarker Discovery grant (no. 19ae0101074s0401 to H.N.) from the Japan Agency for Medical Research and Development (AMED), and the National Cancer Center Research and Development Fund (no. 28-A-7 and 31-A-7 to H.N.).

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All authors contributed to each stage of the preparation of this manuscript.

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Correspondence to Hiroyoshi Nishikawa.

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Competing interests

S.Ko. received research funding from Ono Pharmaceutical and Bristol-Myers Squibb outside this study. H.N. received honoraria and research funding from Ono Pharmaceutical, Chugai Pharmaceutical, MSD and Bristol-Myers Squibb, and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma and BD Japan outside this study. All other authors declare no competing interests.

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Nature Reviews Cancer thanks B. Pollack, F. Skoulidis and N. Ueno for their contribution to the peer review of this work.

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Glossary

Neoantigens

Antigens derived from gene alterations in tumour cells. As they are recognized as foreign bodies by the immune system, strong immune responses are generally induced.

Antibody-dependent cellular cytotoxicity

(ADCC). When antibodies bind to the target cells, especially cancer cells, immune cells such as macrophages and natural killer cells are attracted. These attracted immune cells possess activating Fc receptors that recognize the Fc region of the antibody, and kill the targeted cells to which the antibody binds through releasing cytotoxic molecules.

NKT cells

A type of T cells that also possess the characteristics of natural killer cells. The T cell receptors of natural killer T (NKT) cells recognize glycolipids presented on CD1d molecules as antigens.

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Kumagai, S., Koyama, S. & Nishikawa, H. Antitumour immunity regulated by aberrant ERBB family signalling. Nat Rev Cancer 21, 181–197 (2021). https://doi.org/10.1038/s41568-020-00322-0

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