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CRISPR Screen Uncovers Genes That Help Cancer Cells Evade Immune System

NEW YORK – Researchers have identified more than 100 genes that enable cancer cells to evade the immune system.

Cancer cells typically acquire changes that allow them to go unnoticed and unscathed by immune cells like cytotoxic T lymphocytes, which are charged with defending the host against infection. Circumventing T cells not only allows cancer cells to spread, but can also lead them to become resistant to immunotherapies.

Researchers from Canada and the US used CRISPR-based screening tools to home in on genes that contribute to immune evasion in six cancer cell models. As they reported in Nature on Wednesday, they identified more than 180 genes that, when deleted, make cancer cells either more sensitive or more resistant to T cell-induced toxicity. The screens especially implicated autophagy-associated genes as important for immune evasion, but the researchers also noted that losing some autophagy genes in pairs made cancer cells resistant to T cell activity, a finding that could have implications for treatment.

"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," co-first author Keith Lawson from the University of Toronto said in a statement. 

He and his colleagues conducted genome-wide CRISPR screens of a panel of mouse cancer cell lines, including models of breast, colon, kidney, and skin cancer. The screens targeted more than 19,000 protein-coding genes, and the CRISPR-mutagenized cells were grown in the presence or absence of pre-activated antigen-specific cytotoxic T cells. The researchers then searched for genes that, when perturbed, made the cancer cells more or less sensitive to T cell attacks. 

In all, they identified 182 core cancer intrinsic immune evasion genes.

The researchers confirmed correlations between these core cancer intrinsic immune evasion genes and interferon gamma response, leukocyte fraction, and innate anti-PD1 resistance using data from The Cancer Genome Atlas. In addition, they noted positive correlations between the core T cell suppressor class and lymphocyte infiltration, cytolytic index, lymphocytes, and CD8+ T cell fraction. This, the researchers said, connects the observations they made in the mouse models to human patient data.

The set of 182 immune evasion genes included genes involved in expected pathways such as antigen presentation, Jak-Stat signaling, and NFκB signaling. But it also included a number of genes that had not been associated previously with immune evasion, such as genes involved in autophagy, the recycling of cellular components. In particular, they found the autophagy pathway is needed to resist toxicity induced by the cytokines IFNγ and TNF.

However, the researchers noted that when some autophagy-associated genes were deleted in pairs, those cells became resistant to T cell activity. This finding indicated that treating a patient with an autophagy gene mutation with another therapy targeting a different autophagy gene might be counterproductive and underscores the importance of understanding genetic interactions.

"We found this complete inversion of gene dependency," added senior author Jason Moffat, a professor of medical genetics at Toronto's Donnelly Centre for Cellular and Biomolecular Research, in a statement. "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."