Taking stock of Tumor Necrosis Factor’s role in killing cancer cells

Peter Mac scientists who were investigating how tumours evade the immune system have identified a potent and previously underappreciated way that cancer cells are destroyed, involving Tumor Necrosis Factor (TNF).

The study, led by Dr Jane Oliaro and Professor Ricky Johnstone, highlights the importance of this inflammatory cytokine in destroying cancer cells that may avoid being killed directly by the immune system’s T cells.

The discovery opens a potential new pathway for developing drugs to harness the anti-cancer powers of TNF, particularly to boost the effectiveness of other block-buster immunotherapy drugs.

The results are published online today by the journal Science Immunology.

“T cells can directly kill cancer cells when they recognise antigens on the cancer cell surface but they have another weapon in their arsenal, TNF, which may be very important in fighting cancer,” says Dr Oliaro, Head of Peter Mac’s Immune Defence Laboratory.

“Our study has revealed that the large amounts of TNF produced by T cells when they recognise a cancer cell causes widespread collateral damage to other cancer cells nearby. This means that TNF can kill rogue cells that either don’t have the antigen on their surface, or are hidden from T cells deep within a tumour – a phenomenon we have coined ‘bystander killing’.”

The scientists also captured dramatic time-lapse footage of this “bystander killing” occurring in a dish (Footage available at Dropbox link).

TNF is naturally produced as a result of T cells being activated in response to cancer cells, a virus or other foreign invader – however the importance of TNF bystander killing in the immune system’s ability to fight cancer has largely been overlooked.

The Peter Mac researchers developed a new, whole-genome gene editing screening process using CRISPR methodology to identify key genes and molecular pathways that are important for cancers to evade the immune system.

This involved individually deleting all 20,000 genes in the genome in cancer cells and testing which ones, when missing, allow cancer cells to evade T cell killing. Using a number of different cancer cells and approaches, genes involved in sensitivity to TNF were unanimously the top hits in the screens.

This new method, not performed before on this scale in Australia, was developed by Dr Conor Kearney and Dr Stephin Vervoort who are postdoctoral fellows in the Oliaro and Johnstone labs respectively.

“This whole-genome CRISPR screening process has shown us when tumours evade the immune system, a major reason for this is acquired resistance to TNF killing,” says Professor Johnstone, who is Peter Mac’s Executive Director of Cancer Research.

“This study is a wonderful example of what can be achieved when innovative and collaborative research efforts combine the powerful technology of two disciplines, immunology and genetics, to answer a fundamental question in cancer research – how cancer cells adapt to evade our immune system.”

Work is already underway at Peter Mac on testing a drug that could sensitize tumour cells to TNF. This could provide the key to extending the ground-breaking results that the latest immunotherapy drugs are showing to other solid cancers, and ultimately improve the number of patients that respond to this exciting new therapy.

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