Researchers from Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto, have mapped the genes that allow cancer cells to evade the host immune system. This study provides further insight into the development of immunotherapies.
Evading immune system
Evading the host immune response is a key hallmark of cancer. To evade recognition and destruction by effector cells of the immune system, cancer cells must acquire phenotypic changes. These changes facilitate the expansion and dissemination of cancer cells, but most importantly, promote resistance to immunotherapies and chimeric antigen receptor T cells. Most studies exploring the mechanisms that promote immune evasion are limited to the detection of frequently occurring genetic alterations.
In a study, published in Nature, researchers explored the functional genomic landscape of cancer-intrinsic cytotoxic T cell (CTL) evasion. To do this, they developed and applied loss-of-function CRISPR-Cas9 genetic screening methods on a genome-wide scale. They performed these screens across a panel of functionally and genetically diverse cell lines.
Core set of genes
From this, the team identified a core conserved set of 182 genes and pathways that broadly mediate cancer-intrinsic CTL evasion. The perturbation of such genes, increased either the sensitivity or the resistance of cancer cells to CTL-mediated toxicity. The team also established a central role for genes that negatively regulate the type-II interferon response. Interestingly, they identified that the autophagy pathway is an important mediator of the evasion of CTLs by cancer cells. However, they found that when they deleted certain autophagy genes in pairs, the cells became resistant to T cell killing. This result indicates that genetic context dictates whether introducing second mutations will have no effect, cause resistant or sensitivity to therapy. For example, treating cells that harbour a mutation in one autophagy gene with immunotherapy and a drug targeting another autophagy gene, could in fact make the disease worse.
This data widens our knowledge of the genetic networks involved in cancer immune evasion. This reference set of core CTL-evasion genes and pathways could help inform efforts to develop cancer immunotherapy strategies.
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