Nav: Home

Scientists identify dozens of genes allowing cancer cells to evade the immune system

September 23, 2020

Toronto scientists have mapped the genes allowing cancer cells to avoid getting killed by the immune system in a finding that paves the way for the development of immunotherapies that would be effective for larger patient populations and across different tumour types.

"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 tumour types," says Jason Moffat, a professor of molecular genetics in the
The study also revealed the need for new therapy to take into account the genetic composition of tumours because of mutations in the cancer cells that can potentially make the disease worse in response to treatment, often referred to as cancer resistance mutations.

"It's very important to understand at the molecular level how cancer develops resistance to immunotherapies in order to make them more broadly available. Advances in systematic genetic approaches have let us key in on genes and molecular pathways that are commonly involved in resistance to therapy," says Moffat, who holds Canada Research Chair in Functional Genomics of Cancer.

In immunotherapy, a patient's own immune cells, known as T killer cells, are engineered to find and destroy cancer. But treatment resistance has precluded its use in most patients, especially those with solid tumours.

"It's an ongoing battle between the immune system and cancer, where the immune system is trying to find and kill the cancer whereas the cancer's job is to evade that killing," says Keith Lawson, a co-lead author completing a PhD in Moffat's lab as part of his medical training in the Surgeon-Scientist Program at U of T's Faculty of Medicine.

Tumour heterogeneity--genetic variation in tumour cells within and across individuals that can impact therapy response--further complicates things.

"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," says Lawson.

The team, including collaborators from Agios Pharmaceuticals in Cambridge, Massachusetts, looked for genes that regulate immune evasion across six genetically diverse tumor models derived from breast, colon, kidney and skin cancer. The cancer cells were placed in a dish alongside the T cells engineered to kill them, where the ensuing onslaught served as a baseline. The researchers next deployed the gene editing tool CRISPR to switch off one-by-one every gene in the cancer cells and measured the resulting deviations from the killing baseline.

They identified 182 "core cancer intrinsic immune evasion genes" whose deletion makes the cells either more sensitive or more resistant to T cell attack. Among the resisters were all the genes known to develop mutations in patients who stopped responding to immunotherapy, giving the researchers confidence that their approach worked.

Many of the found genes 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", says Lawson.

Genes involved in autophagy, a process when cells ramp up recycling their components to mitigate damage following stress, came up as key for immune evasion. This raises a possibility that cancer's susceptibility to immunotherapy could be boosted by targeting its autophagy genes.

But as the researchers delved deeper, they found that deleting certain autophagy genes in pairs rendered the cells resistant to T cell killing. It means that if a tumour already harbors a mutation in one autophagy gene, a treatment that combines immunotherapy with a drug targeting another autophagy gene could make the disease worse in that patient.

"We found this complete inversion of gene dependency", says Moffat. "We did not anticipate this at all. What it shows us is that genetic context, what mutations are present, very much dictates whether the introduction of the second mutations will cause no effect, resistance or sensitivity to therapy".

As more research explores combinatorial effects of mutations across different types of cancer cells, it should become possible to predict from a tumour's DNA what type of therapy will be most effective.

University of Toronto

Related Science Articles:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.
Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.
Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.
Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.
World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.
PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.
Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.
Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.
More Science News and Science Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at     You can read The Transition Integrity Project's report here.