dinaciclib and Adenocarcinoma

Adaptive immune resistance mediated by the cytokine interferon gamma (IFNG) still constitutes a major problem in cancer immunotherapy. We develop strategies for overcoming IFNG-mediated adaptive immune resistance in pancreatic ductal adenocarcinoma cancer (PDAC).. We screened 429 kinase inhibitors for blocking IFNG-induced immune checkpoint (indoleamine 2,3-dioxygenase 1 (IDO1) and CD274) expression in a human PDAC cell line. We evaluated the ability of the cyclin-dependent kinase (CDK) inhibitor dinaciclib to block IFNG-induced. Pharmacological (using dinaciclib) or genetic (using shRNA or siRNA) inactivation of CDK1/2/5 not only blocks JUN-dependent immune checkpoint expression, but also triggers histone-dependent immunogenic cell death in immortalised or primary cancer cells in response to IFNG. This dual mechanism turns an immunologically 'cold' tumour microenvironment into a 'hot' one, dramatically improving overall survival rates in mouse pancreatic tumour models (subcutaneous, orthotopic and transgenic models). The abnormal expression of CDK1/2/5 and IDO1 was associated with poor patient survival in several cancer types, including PDAC.. CDK1/2/5 kinase activity is essential for IFNG-mediated cancer immunoevasion. CDK1/2/5 inhibition by dinaciclib provides a novel strategy to overcome IFNG-triggered acquired resistance in pancreatic tumour immunity.

Topics: Adaptive Immunity; Adenocarcinoma; Animals; B7-H1 Antigen; Carcinoma, Pancreatic Ductal; CDC2 Protein Kinase; Cell Death; Cell Line, Tumor; Cyclic N-Oxides; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 5; Gene Expression; Humans; Immune Checkpoint Inhibitors; Indolizines; Interferon-gamma; Mice; Pancreatic Neoplasms; Peptide Fragments; Pyridinium Compounds; Signal Transduction; Survival Rate; Tumor Microenvironment

Blockade of the checkpoint inhibitor programmed death 1 (PD1) has demonstrated remarkable success in the clinic for the treatment of cancer; however, a majority of tumors are resistant to anti-PD1 monotherapy. Numerous ongoing clinical combination therapy studies will likely reveal additional therapeutics that complement anti-PD1 blockade. Recent studies found that immunogenic cell death (ICD) improves T cell responses against different tumors, thus indicating that ICD may further augment antitumor immunity elicited by anti-PD1. Here, we observed antitumor activity following combinatorial therapy with anti-PD1 Ab and the cyclin-dependent kinase inhibitor dinaciclib in immunocompetent mouse tumor models. Dinaciclib induced a type I IFN gene signature within the tumor, leading us to hypothesize that dinaciclib potentiates the effects of anti-PD1 by eliciting ICD. Indeed, tumor cells treated with dinaciclib showed the hallmarks of ICD including surface calreticulin expression and release of high mobility group box 1 (HMGB1) and ATP. Mice treated with both anti-PD1 and dinaciclib showed increased T cell infiltration and DC activation within the tumor, indicating that this combination improves the overall quality of the immune response generated. These findings identify a potential mechanism for the observed benefit of combining dinaciclib and anti-PD1, in which dinaciclib induces ICD, thereby converting the tumor cell into an endogenous vaccine and boosting the effects of anti-PD1.

Topics: Adenocarcinoma; Adenosine Triphosphate; Animals; Antibodies, Monoclonal; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; CD8-Positive T-Lymphocytes; Cell Death; Cell Line, Tumor; Cyclic N-Oxides; Cytokines; Dendritic Cells; Drug Synergism; Female; HMGB1 Protein; Immune System; Immunotherapy; Indolizines; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Transplantation; Phagocytosis; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridinium Compounds