1. Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression
- Author
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Marlene C. Hinton, Dewan Md Sakib Hossain, Wendy M. Blumenschein, Sarah Javaid, Anandi Sawant, Jeff Grein, Alissa A. Chackerian, Chunsheng Zhang, Mingmei Cai, Manjiri Sathe, and Elaine M. Pinheiro
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Apoptosis ,Pyridinium Compounds ,CD8-Positive T-Lymphocytes ,Mice ,chemistry.chemical_compound ,Adenosine Triphosphate ,0302 clinical medicine ,Cancer immunotherapy ,Medicine ,HMGB1 Protein ,Mice, Knockout ,Mice, Inbred BALB C ,Cell Death ,Indolizines ,Antibodies, Monoclonal ,Drug Synergism ,General Medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cytokines ,Immunogenic cell death ,Female ,Immunotherapy ,Research Article ,Combination therapy ,T cell ,Adenocarcinoma ,Cyclic N-Oxides ,03 medical and health sciences ,Immune system ,Phagocytosis ,Cell Line, Tumor ,Animals ,Dinaciclib ,Protein Kinase Inhibitors ,business.industry ,Dendritic Cells ,Bridged Bicyclo Compounds, Heterocyclic ,Blockade ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Immune System ,Cancer research ,business ,Neoplasm Transplantation - Abstract
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.
- Published
- 2018
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