CXCR2 inhibition enhances anti-PD1 immunotherapy in a mouse model of pancreatic cancer

Version française

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 [1]. 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 [4].

 

The main findings were as follows:

 

  1. In the mouse KPC model of pancreatic cancer (KrasG12D/+, Trp53R172H/+ (mouse p53) ) CXCR2 deletion prevented metastasis almost completely.
  2. 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.
  3. CXCR2 inhibition reduced the number of immuno-inhibitory cells at metastatic niches such as the liver.
  4. CXCR2 inhibition and deletion increased the number of CD3+ T cells (activated) in pancreatic tumours.
  5. 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 [5] and suggests the broader importance of modifying the stroma in combination with immunotherapy for pancreatic cancer.

 

Refs

 

  1. https://pharmaceuticalintelligence.com/2016/04/19/targeting-emt-as-a-therapy-strategy-for-pancreatic-cancer/
  2. 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.
  3. 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.
  4. 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.
  5. 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.
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