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

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.

Fig. 1 |. Classical IFNγ producers in the tumour microenvironment.

The spatial pattern of interferon-γ (IFNγ) release by T helper 1 (T_H1) cells, cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. T_H1 cells release IFNγ, interleukin-2 (IL-2), granulocyte–monocyte colony-stimulating factor (GM-CSF) and lymphotoxin-α (LTα) in a concentrated manner within the antigen-presenting cell (APC)–T_H1 cell synapse (synaptic release). Tumour necrosis factor (TNF) is released in many directions, both towards and away from the synapse (multidirectional release). CTLs release IFNγ towards the synapse but the release is not well directed, allowing IFNγ to exert effects on cells beyond, but near, the synapse (leaky synaptic release). The release of TNF and perforin is synaptic. NK cells release IFNγ in a multidirectional manner.

Fig. 2 |. IFNγ responders in the tumour microenvironment.

Interferon-γ (IFNγ)-induced signalling occurs in many types of immune cells (such as T helper 1 (T_H1) cells, cytotoxic T lymphocytes (CTLs), antigen-presenting cells (APCs), regulatory T (T_reg) cells and natural killer (NK) cells) and non-immune cells (vasculature and tumour cells) within the tumour microenvironment. Key proteins upregulated by IFNγ and the interacting ligands and receptors are shown. The biological consequences of IFNγ-induced signalling in each cell type are summarized in boxes. IFNγ responses that make these cell types teammates are in green, whereas responses that make them opponents are in red. CXCR3, CXC-chemokine receptor 3; cDC1, conventional type 1 dendritic cell; FASL, FAS ligand; GC, germinal centre; IDO1, indoleamine 2,3-dioxygenase 1; IL-12R, interleukin-12 receptor; IFNGR, interferon-γ receptor; NO, nitric oxide; PD1, programmed cell death 1; PDL1, programmed cell death 1 ligand 1; pSTAT1, phosphorylated signal transducer and activator of transcription 1; TCR, T cell receptor.