IFNɣ in tumour immunity – from friend to foe

Exceptionally at 11h30 am.

The cytokine IFNγ, produced mainly by Natural Killer and CD8 T cells, is central to anti-tumour immunity. IFNγ-related gene signature is a predictive marker for chemotherapy, radiotherapy and immunotherapy efficiency in multiple tumour types. Mechanistically, IFNγ inhibits tumour proliferation and angiogenesis, and increases the expression of MHC molecules, allowing direct killing by cytotoxic T-cells. As a result, many tumours escape immunosurveillance by acquiring mutations and deletions in the IFNγ signalling pathway, limiting cancer recognition and killing by CD8 T-cells. This has been for example observed in patients who become secondary refractory to checkpoint blockade after initially responding to treatment. But several lines of evidence also point to IFNγ as a factor restricting tumour immunity in humans and mice, promoting tumour growth and immune evasion. As a result, cancer therapies based on recombinant IFNγ treatment are rarely effective. Because IFNγ is inherently linked to the efficiency of tumour immunity, it is critical to understand how it can also simultaneously impede tumour immunity.

In this talk, I will provide evidence that IFNγ directly acts on immune cells, in particular, CD8 T cells, to restrict anti-tumour responses, initiating a negative feedback loop contributing to restricting anti-tumour immunity. I will then move on and explore the hypothesis that the immune landscape is able to adapt in space and time to IFNγ-dependent tumour escape. Counter-intuitively, this adaptation results in enhanced immune fitness, explaining some of the discrepancies in the role of IFNγ signalling in tumours, especially for the efficacy of checkpoint blockade.

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