Genome-wide CRISPR screens define determinants of epithelial-mesenchymal transition mediated immune evasion by pancreatic cancer cells

The genetic circuits that allow cancer cells to evade immune killing via epithelial mesenchymal plasticity remain poorly understood. Here, we showed that mesenchymal-like (Mes) KPC3 pancreatic cancer cells were more resistant to cytotoxic T lymphocyte (CTL)-mediated killing than the parental epithelial-like (Epi) cells and used parallel genome-wide CRISPR screens to assess the molecular underpinnings of this difference. Core CTL-evasion genes (such as IFN-? pathway components) were clearly evident in both types. Moreover, we identified and validated multiple Mes-specific regulators of cytotoxicity, such as Egfr and Mfge8. Both genes were significantly higher expressed in Mes cancer cells, and their depletion sensitized Mes cancer cells to CTL-mediated killing. Notably, Mes cancer cells secreted more Mfge8 to inhibit proliferation of CD8(+) T cells and production of IFN-? and TNFa. Clinically, increased Egfr and Mfge8 expression was correlated with a worse prognosis. Thus, Mes cancer cells use Egfr-mediated intrinsic and Mfge8-mediated extrinsic mechanisms to facilitate immune escape from CD8(+) T cells.

Automated summary

The genetic circuits allowing cancer cells to evade immune killing through epithelial mesenchymal plasticity are poorly understood. This study found that mesenchymal-like pancreatic cancer cells were more resistant to cytotoxic T lymphocyte (CTL)-mediated killing than epithelial-like cells. Genome-wide CRISPR screens were used to identify the molecular mechanisms underlying this difference. It was discovered that Mes-specific regulators such as Egfr and Mfge8 facilitate immune escape from CD8(+) T cells by inhibiting their proliferation and the production of immune signaling molecules.