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Interferon-γ: teammate or opponent in the tumour microenvironment?

Nature Reviews Immunology volume 22, pages 158–172 (2022)Cite this article

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Abstract

Cancer immunotherapy offers substantive benefit to patients with various tumour types, in some cases leading to complete tumour clearance. However, many patients do not respond to immunotherapy, galvanizing the field to define the mechanisms of pre-existing and acquired resistance. Interferon-γ (IFNγ) is a cytokine that has both protumour and antitumour activities, suggesting that it may serve as a nexus for responsiveness to immunotherapy. Many cancer immunotherapies and chemotherapies induce IFNγ production by various cell types, including activated T cells and natural killer cells. Patients resistant to these therapies commonly have molecular aberrations in the IFNγ signalling pathway or express resistance molecules driven by IFNγ. Given that all nucleated cells can respond to IFNγ, the functional consequences of IFNγ production need to be carefully dissected on a cell-by-cell basis. Here, we review the cells that produce IFNγ and the different effects of IFNγ in the tumour microenvironment, highlighting the pleiotropic nature of this multifunctional and abundant cytokine.

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Fig. 1: Classical IFNγ producers in the tumour microenvironment.
Fig. 2: IFNγ responders in the tumour microenvironment.

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Acknowledgements

The authors thank everyone in the Vignali laboratory for all their constructive comments and advice. This work was supported by the US National Institutes of Health (F32 CA247004-01 and T32 CA082084 to A.M.G.; P01 AI108545, R01 CA203689 and P30 CA047904 to D.A.A.V.).

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Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Angela M. Gocher, Creg J. Workman & Dario A. A. Vignali

  2. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Angela M. Gocher, Creg J. Workman & Dario A. A. Vignali

  3. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Dario A. A. Vignali

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The authors contributed equally to all aspects of the article.

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Correspondence to Dario A. A. Vignali.

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Competing interests

D.A.A.V. is a co-founder and shareholder of Novasenta and Tizona, a shareholder of Oncorus and Werewolf, has patents licensed and receives royalties from Astellas and Bristol Myers Squibb, is a scientific advisory board member for Tizona, Werewolf, F-Star and Bicara, is a consultant for Astellas, Bristol Myers Squibb, Almirall and Incyte, and receives research funding from Bristol Myers Squibb, Astellas and Novasenta. The other authors declare no competing interests.

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Glossary

Programmed cell death 1 ligand 1

(PDL1). A ligand that binds to programmed cell death 1 (PD1) on T cells to inhibit their activation, proliferation and cytokine production. PDL1 is also known as CD274 and B7-H1, and PDL2 is also known as CD273 or B7-C.

Epigenetic regulation

Control of gene expression through phenotypic changes that do not alter the DNA sequence. Examples include DNA methylation, histone modifications, microRNAs, long non-coding RNAs and nucleosome positioning.

Invariant NK T cells

(iNKT cells). Innate-like T cells that express a T cell receptor α-chain that recognizes lipid antigens presented by the non-classical MHC molecule CD1d expressed on dendritic cells.

γδ T cells

T cells that express T cell receptor γ and δ chains and represent 1–4% of the T cell population. They produce interferon-γ (IFNγ) rapidly following activation in a non-MHC-restricted manner by tumour-derived lipids, glycoproteins and phosphorus-containing compounds.

Adaptive immune resistance

The upregulation of immunosuppressive mechanisms in response to chronic proinflammatory stimuli.

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Gocher, A.M., Workman, C.J. & Vignali, D.A.A. Interferon-γ: teammate or opponent in the tumour microenvironment?. Nat Rev Immunol 22, 158–172 (2022). https://doi.org/10.1038/s41577-021-00566-3

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