DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma
| Autor: | shubhendu Trivedi, Sandra A. Jablonski, Elana J. Fertig, Vince O'Neill, Allison A. Fitzgerald, Louis M. Weiner, Shangzi Wang, Melanie Loth, Veena R Agarwal, Eugene Zhukovsky, Emily F Marcisak, John MacDougall, Annie Zuo, Dimple Bhatia |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Receptors CXCR3 T-Lymphocytes medicine.medical_treatment T cell th1-th2 balance Immunology Adenocarcinoma CD8-Positive T-Lymphocytes CXCR3 programmed cell death 1 receptor Mice Immune system drug evaluation preclinical Tumor Microenvironment medicine Animals Humans Immunology and Allergy Cytotoxic T cell RC254-282 combination Pharmacology Dipeptidyl-Peptidase IV Inhibitors Tumor microenvironment business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Basic Tumor Immunology Immunotherapy drug therapy Killer Cells Natural Disease Models Animal Cytokine medicine.anatomical_structure Oncology Cancer research Molecular Medicine business CD8 Carcinoma Pancreatic Ductal |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 11 (2021) Journal for Immunotherapy of Cancer |
| ISSN: | 2051-1426 |
| Popis: | BackgroundPancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the USA by 2030. Immune checkpoint inhibitors fail to control most PDAC tumors because of PDAC’s extensive immunosuppressive microenvironment and poor immune infiltration, a phenotype also seen in other non-inflamed (ie, ‘cold’) tumors. Identifying novel ways to enhance immunotherapy efficacy in PDAC is critical. Dipeptidyl peptidase (DPP) inhibition can enhance immunotherapy efficacy in other cancer types; however, the impact of DPP inhibition on PDAC tumors remains unexplored.MethodsWe examined the effects of an oral small molecule DPP inhibitor (BXCL701) on PDAC tumor growth using mT3-2D and Pan02 subcutaneous syngeneic murine models in C57BL/6 mice. We explored the effects of DPP inhibition on the tumor immune landscape using RNAseq, immunohistochemistry, cytokine evaluation and flow cytometry. We then tested if BXCL701 enhanced anti-programmed cell death protein 1 (anti-PD1) efficacy and performed immune cell depletion and rechallenged studies to explore the relevance of cytotoxic immune cells to combination treatment efficacy.ResultsIn both murine models of PDAC, DPP inhibition enhanced NK and T cell immune infiltration and reduced tumor growth. DPP inhibition also enhanced the efficacy of anti-PD1. The efficacy of dual anti-PD1 and BXCL701 therapy was dependent on both CD8+ T cells and NK cells. Mice treated with this combination therapy developed antitumor immune memory that cleared some tumors after re-exposure. Lastly, we used The Cancer Genome Atlas (TCGA) to demonstrate that increased NK cell content, but not T cell content, in human PDAC tumors is correlated with longer overall survival. We propose that broad DPP inhibition enhances antitumor immune response via two mechanisms: (1) DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3+ NK and T cells, and (2) DPP8/9 inhibition activates the inflammasome, resulting in proinflammatory cytokine release and Th1 response, further enhancing the CXCL9/10-CXCR3 axis.ConclusionsThese findings show that DPP inhibition with BXCL701 represents a pharmacologic strategy to increase the tumor microenvironment immune cell content to improve anti-PD1 efficacy in PDAC, suggesting BXCL701 can enhance immunotherapy efficacy in ‘cold’ tumor types. These findings also highlight the potential importance of NK cells along with T cells in regulating PDAC tumor growth. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|