Targeting tumor-intrinsic CDK1/Cyclin B1 complex improves responses to immunotherapy in pancreatic cancer.

Immunotherapies, especially immune checkpoint blockade, has achieved considerable success in multiple cancers; however, patients with "cold tumors", in particular pancreatic cancer, rarely respond, largely due to insufficient T cell activation and infiltration within the tumor microenvironment (TME). To understand the mechanisms whereby tumor cells regulate T cell activation, we conducted an in vivo CRISPR-Cas9 screen, and identified the CDK1/Cyclin B1 complex as a previously unrecognized tumor-intrinsic driver of immune evasion in pancreatic cancer. Genetic ablation or pharmacological inhibition of the CDK1/Cyclin B1 complex induced a T cell-inflamed TME, which synergized with PD-1 blockade to suppress tumor growth. Mechanistically, loss of Ccnb1 reduced phosphorylation of the retinoblastoma protein (Rb) at S249/T252 residues, and restored NF-κB activity, which elevated the production of granulocyte-macrophage colony-stimulating factor (GM-CSF), and promoted the recruitment and activation of conventional type 1 dendritic cells. Collectively, these findings uncover the CDK1/Cyclin B1 complex involved in tumor immune evasion and provide a compelling rationale for combining CDK1/Cyclin B1 inhibition with PD-1 blockade in the treatment of pancreatic cancer.