More and more research reveals cancer’s various tactics and evasion strategies. Cancer has been found to evade therapy through hijacking, camouflaging, and resisting. But as more studies reveal its dirty tricks, it also opens the door to preventing the culprits and paving the way for more new and effective immunotherapies. Scientists from the University of Toronto (UofT) have recently identified genes allowing cancer cells to avoid getting killed by the immune system; 182 genes to be exact.
Their findings, “Functional genomic landscape of cancer-intrinsic evasion of killing by T cells,” in the journal Nature and led by Jason Moffat, PhD, a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at UofT, Canada research chair in functional genomics of cancer, and CSO at Empirica Therapeutics.
“Over the last decade, different forms of immunotherapy have emerged as really potent cancer treatments but the reality is that they only generate durable responses in a fraction of patients and not for all tumor types,” explained Moffat.
“The genetic circuits that allow cancer cells to evade destruction by the host immune system remain poorly understood. Here, to identify a phenotypically robust core set of genes and pathways that enable cancer cells to evade killing mediated by cytotoxic T lymphocytes (CTLs), we performed genome-wide CRISPR screens across a panel of genetically diverse mouse cancer cell lines that were cultured in the presence of CTLs,” noted the researchers.
The researchers, along with collaborators from Agios Pharmaceuticals, looked for genes that regulate immune evasion across six genetically diverse tumor models derived from breast, colon, kidney, and skin cancer.
“It’s important to not just find genes that can regulate immune evasion in one model of cancer, but what you really want are to find those genes that you can manipulate in cancer cells across many models because those are going to make the best therapeutic targets,” explained Keith Lawson, a coauthor who is completing a PhD in Moffat’s lab as part of his medical training in the surgeon-scientist program at UofT’s Faculty of Medicine.
The cancer cells were placed in a dish alongside the T cells engineered to kill them, serving as a baseline. The researchers then used CRISPR to switch “off” one by one every gene in the cancer cells and measured the resulting deviations from the killing baseline.
The researchers identified a core set of 182 genes across mouse cancer models, whose deletion increased either the sensitivity or the resistance of cancer cells to CTL-mediated toxicity. They observed genes known to develop mutations in patients who stopped responding to immunotherapy present, confirming their approach worked. Many of genes found had no previous links to immune evasion.
“That was really exciting to see, because it means that our dataset was very rich in new biological information,” stated Lawson.
Additionally, the researchers identified the autophagy pathway as a conserved mediator of the evasion of CTLs by cancer cells, and showed that the pathway is required to resist cytotoxicity induced by the cytokines IFNγ and TNF. If a tumor already harbors a mutation in one autophagy gene, the disease may be worsened in a patient if they are given a treatment that combines immunotherapy with a drug targeting another autophagy gene.
“Through the mapping of cytokine- and CTL-based genetic interactions, together with in vivo CRISPR screens, we show how the pleiotropic effects of autophagy control cancer-cell-intrinsic evasion of killing by CTLs and we highlight the importance of these effects within the tumor microenvironment,” concluded the researchers.
Their findings demonstrate the need for the development of new therapies that target the genetic composition of tumors due to cancer-resistant mutations.
