Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer
Authors: Jun Zhao
Baozhong Shen
Tingting Li
Li Tian
Chun Li
Chunyu Xu
Weiyi Peng
Xiaofei Wen
Xiaoxia Wen
Sanjay Gupta
Marites P Melancon
Journal: Nature Communications (2019)
Discipline: Multidisciplinary
Keywords: Immunotherapy; pancreatic ductal adenocarcinoma (PDAC); stroma; irreversible electroporation (IRE); immunogenic cell death
Affiliations: Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA., Molecular Imaging Research Center of Harbin Medical University, Harbin, 150001, Heilongjiang, China., Department of Interventional Radiology, Fourth Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China., Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Biophysics, School of Life Science & Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, China., Department of Melanoma Medical Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA., Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. .

Abstract:  Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) due to the presence of an immunosuppressive tumor-associated stroma. Here, we demonstrate an effective modulation of that stroma by irreversible electroporation (IRE), a local ablation technique that has received regulatory approval in the United States. IRE induces immunogenic cell death, activates dendritic cells, and alleviates stroma-induced immunosuppression without depleting tumor-restraining collagen. The combination of IRE and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint blockade promotes selective tumor infiltration by CD8+ T cells and significantly prolongs survival in a murine orthotopic PDAC model with a long-term memory immune response. Our results suggest that IRE is a promising approach to potentiate the efficacy of immune checkpoint blockade in PDAC. 

Retracted: No

PubPeer comments:
  I am wondering why the authors considered in fig. 4C the **(CD44u2212CD62Lu2212) cells as  effector cells and (CD44+CD62Lu2212) cells as  memory cells (I guess  central memory cells)** when it is well known (and the reference they attach [Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187u20132194 (2010)] states the same in fig. 2, but see also Mueller, S. N., Gebhardt, T., Carbone, F. R., Heath, W. R. (2013). Memory T Cell Subsets, Migration Patterns, and Tissue Residence. Annual Review of Immunology, 31(1), 137u2013161.) that **effector effector memory cells are (CD44+CD62L-) while central memory ones are (CD44+CD62L+)**. In this case it would appear as electroporation caused an increase in both types. In this case it would also be strange since untreated PDACs would express more central memory T cells than effector effector memory ones, while many other papers show the opposite (see PMID: 23233419 and 27797936). ,