The stromal microenvironment is a major barrier to effective pancreatic cancer therapies. New drugs with novel mechanisms of action are required to reduce the stromal density and block its immunosuppressive functions . CXCR2 promotes the migration of neutrophils and myeloid-derived suppressor cells (MDSCs) to sites of inflammation such as pancreatic cancer tumours [2, 3]. A recent study set out to determine the exact role of CXCR2 in a mouse model of pancreatic cancer .
The main findings were as follows:
- In the mouse KPC model of pancreatic cancer (KrasG12D/+, Trp53R172H/+ (mouse p53) ) CXCR2 deletion prevented metastasis almost completely.
- Deletion of Ly6G+ cells which include neutrophils and MDSCs resulted in a recapitulation of the effects of CXCR2 inhibition suggesting that these cells mediate the effects of CXCR2.
- CXCR2 inhibition reduced the number of immuno-inhibitory cells at metastatic niches such as the liver.
- CXCR2 inhibition and deletion increased the number of CD3+ T cells (activated) in pancreatic tumours.
- Combination of CXCR2 inhibitor and anti-PD1 immune checkpoint inhibitor significantly improved survival compared with anti-PD1 alone.
Point 5 is important because previous attempts to treat PDAC with checkpoint inhibitors have been unsuccessful  and suggests the broader importance of modifying the stroma in combination with immunotherapy for pancreatic cancer.
Eash, Kyle J., Adam M. Greenbaum, Priya K. Gopalan, and Daniel C. Link. ‘CXCR2 and CXCR4 Antagonistically Regulate Neutrophil Trafficking from Murine Bone Marrow’. Journal of Clinical Investigation 120, no. 7 (1 July 2010): 2423–31. doi:10.1172/JCI41649.
- Highfill, Steven L., Yongzhi Cui, Amber J. Giles, Jillian P. Smith, Hua Zhang, Elizabeth Morse, Rosandra N. Kaplan, and Crystal L. Mackall. ‘Disruption of CXCR2-Mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy’. Science Translational Medicine 6, no. 237 (21 May 2014): 237ra67. doi:10.1126/scitranslmed.3007974.
- Steele, Colin W., Saadia A. Karim, Joshua D.G. Leach, Peter Bailey, Rosanna Upstill-Goddard, Loveena Rishi, Mona Foth, et al. ‘CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma’. Cancer Cell, June 2016. doi:10.1016/j.ccell.2016.04.014.
- Winograd, R., K. T. Byrne, R. A. Evans, P. M. Odorizzi, A. R. L. Meyer, D. L. Bajor, C. Clendenin, et al. ‘Induction of T-Cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma’. Cancer Immunology Research 3, no. 4 (1 April 2015): 399–411. doi:10.1158/2326-6066.CIR-14-0215.