INSIDER is a new series that aims to highlight exciting developments from the world of cancer research and clinical trials. These posts are written by our research laboratory heads and the opinions expressed in these posts are those of the contributing author.

By Prof Matthias Ernst, ONJCRI Director and Head of the Cancer and Inflammation Laboratory

Immunotherapy has without a doubt provided a quantum leap to the treatment of cancer not seen since the introduction of chemotherapy in the 1960’s. Our understanding on how we can re-engage a patient’s immune system to kill cancer cells is continuously being refined, since the ground-breaking work by the 2018 Nobel laureates Tasuku Honjo and James Allison and the many seminal contributions of immunologists, molecular biologists and oncologists before and after them. However, we still need to go a long way before we can deploy the exquisite power and specificity of the immune system to control a majority of cancer.

A recent study published in Nature by a team at the University of Toronto suggests that there is a potentially dazzling number of genes in cancer cells that enable them to evade being killed by the soldiers of the immune system, so called cytotoxic T lymphocytes (CTL). The team around Jason Moffat used a Nobel Prize awarded genome editing technique called CRISPR to inactivate each gene in tumour cells derived from genetically diverse models of breast, colon, kidney, and skin cancer to ask which gene prevents the killing of cancer cells when put together in a culture dish with CTLs.

When looking across all tumour models, the researchers identified nearly 200 genes, whose deletion altered the sensitivity or the resistance of cancer cells to CTL-mediated killing.

The team was able to validate their experimental approach because they identified genes already known to be mutated in patients who stopped responding to immunotherapy, confirming that their experimental approach worked. However, most surprisingly many of the genes they found were never before linked to evasion of cancer cell detection and killing by CTL such as cancer cell autophagy, a conserved pathway activated by distressed cells. Indeed, induction of autophagy in cancer cells made them resistant to cell CTL killing induced by the cytokines IFNγ and TNF.

The findings of this paper powerfully illustrate how the combination of large-scale screening efforts, together with already existing extensive cancer genome information, allows us to identify a plethora of potential new targets to further improve immunotherapy. The challenge will be to filter through the many candidates targets to strategically invest in those that are ultimately providing the broadest benefit to cancer patients.

Source:  NATURE, Vol 586, pages120–126 (2020); KA Lawson et al Functional genomic landscape of cancer-intrinsic evasion of killing by T cells”