Modulation of T cell immune checkpoints combined with inhibition of chemokine receptors on myeloid-derived suppressor cells can reprogram the highly suppressive tumor immune microenvironment of pancreatic ductal adenocarcinoma (PDAC), and generates durable complete responses in a PDAC mouse model. These results provide a testable clinical regimen for human PDAC.
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Ying, H. et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 30, 355–385 (2016). A review article that presents the key mechanisms underlying growth, metastasis and therapeutic resistance of PDAC, including the complexity of immune regulation in the tumor microenvironment.
Bear, A. S., Vonderheide, R. H. & O’Hara, M. H. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell 38, 788–802 (2020). A review article that describes strategies that may be rationally combined to overcome immune resistance in PDAC.
O’Reilly, E. M. et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma. JAMA Oncol. 5, 1431–1438 (2019). This paper reports the lack of clinical efficacy of anti-PD1 and anti-CTLA4 immunotherapy in PDAC.
Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016). This paper provides the pre-clinical rationale for targeting CXCR2 on myeloid cells in combination with immunotherapy in PDAC.
Van Der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8+ T cell states in human cancer: insights from single cell analysis. Nat. Rev. Cancer 20, 218–232 (2020). A review article that describes the relationship between various T cell states and therapeutic response to ICT.
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This is a summary of: Gulhati, P. et al. Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumour immunity and durable response in pancreatic cancer. Nat. Cancer https://doi.org/10.1038/s43018-022-00500-z (2022).
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Targeting T cell checkpoints and myeloid suppressor cells is effective in pancreatic cancer. Nat Cancer 4, 7–8 (2023). https://doi.org/10.1038/s43018-022-00501-y