Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer model
Pancreatic cancer is a significant cause of cancer-related mortality and often presents with limited treatment options. Pancreatic tumors are also notorious for their immunosuppressive microenvironment. Irreversible electroporation (IRE) is a non-thermal tumor ablation modality that employs high-vol...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-04-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1352821/full |
| _version_ | 1827276699325169664 |
|---|---|
| author | Khan Mohammad Imran Rebecca M. Brock Natalie Beitel-White Natalie Beitel-White Manali Powar Katie Orr Kenneth N. Aycock Nastaran Alinezhadbalalami Zaid S. Salameh Paige Eversole Benjamin Tintera Justin Markov Madanick Alissa Hendricks-Wenger Sheryl Coutermarsh-Ott Rafael V. Davalos Irving C. Allen Irving C. Allen Irving C. Allen |
| author_facet | Khan Mohammad Imran Rebecca M. Brock Natalie Beitel-White Natalie Beitel-White Manali Powar Katie Orr Kenneth N. Aycock Nastaran Alinezhadbalalami Zaid S. Salameh Paige Eversole Benjamin Tintera Justin Markov Madanick Alissa Hendricks-Wenger Sheryl Coutermarsh-Ott Rafael V. Davalos Irving C. Allen Irving C. Allen Irving C. Allen |
| author_sort | Khan Mohammad Imran |
| collection | DOAJ |
| description | Pancreatic cancer is a significant cause of cancer-related mortality and often presents with limited treatment options. Pancreatic tumors are also notorious for their immunosuppressive microenvironment. Irreversible electroporation (IRE) is a non-thermal tumor ablation modality that employs high-voltage microsecond pulses to transiently permeabilize cell membranes, ultimately inducing cell death. However, the understanding of IRE’s impact beyond the initiation of focal cell death in tumor tissue remains limited. In this study, we demonstrate that IRE triggers a unique mix of cell death pathways and orchestrates a shift in the local tumor microenvironment driven, in part, by reducing the myeloid-derived suppressor cell (MDSC) and regulatory T cell populations and increasing cytotoxic T lymphocytes and neutrophils. We further show that IRE drives induce cell cycle arrest at the G0/G1 phase in vitro and promote inflammatory cell death pathways consistent with pyroptosis and programmed necrosis in vivo. IRE-treated mice exhibited a substantial extension in progression-free survival. However, within a span of 14 days, the tumor immune cell populations reverted to their pre-treatment composition, which resulted in an attenuation of the systemic immune response targeting contralateral tumors and ultimately resulting in tumor regrowth. Mechanistically, we show that IRE augments IFN- γ signaling, resulting in the up-regulation of the PD-L1 checkpoint in pancreatic cancer cells. Together, these findings shed light on potential mechanisms of tumor regrowth following IRE treatment and offer insights into co-therapeutic targets to improve treatment strategies. |
| first_indexed | 2024-04-24T07:04:10Z |
| format | Article |
| id | doaj.art-4cfc1c9636b64b36a522968bb51b419f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-24T07:04:10Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-4cfc1c9636b64b36a522968bb51b419f2024-04-22T05:09:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-04-011510.3389/fimmu.2024.13528211352821Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer modelKhan Mohammad Imran0Rebecca M. Brock1Natalie Beitel-White2Natalie Beitel-White3Manali Powar4Katie Orr5Kenneth N. Aycock6Nastaran Alinezhadbalalami7Zaid S. Salameh8Paige Eversole9Benjamin Tintera10Justin Markov Madanick11Alissa Hendricks-Wenger12Sheryl Coutermarsh-Ott13Rafael V. Davalos14Irving C. Allen15Irving C. Allen16Irving C. Allen17Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, United StatesMedicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, United StatesDepartment of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesMedicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, United StatesDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, United StatesDepartment of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesVirginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Surgery, Carilion Clinic and Virginia Tech Carilion School of Medicine, Roanoke, VA, United StatesDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, United StatesMedicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, United StatesDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, United StatesDepartment of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesMedicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, United StatesDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, United StatesDepartment of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, United StatesPancreatic cancer is a significant cause of cancer-related mortality and often presents with limited treatment options. Pancreatic tumors are also notorious for their immunosuppressive microenvironment. Irreversible electroporation (IRE) is a non-thermal tumor ablation modality that employs high-voltage microsecond pulses to transiently permeabilize cell membranes, ultimately inducing cell death. However, the understanding of IRE’s impact beyond the initiation of focal cell death in tumor tissue remains limited. In this study, we demonstrate that IRE triggers a unique mix of cell death pathways and orchestrates a shift in the local tumor microenvironment driven, in part, by reducing the myeloid-derived suppressor cell (MDSC) and regulatory T cell populations and increasing cytotoxic T lymphocytes and neutrophils. We further show that IRE drives induce cell cycle arrest at the G0/G1 phase in vitro and promote inflammatory cell death pathways consistent with pyroptosis and programmed necrosis in vivo. IRE-treated mice exhibited a substantial extension in progression-free survival. However, within a span of 14 days, the tumor immune cell populations reverted to their pre-treatment composition, which resulted in an attenuation of the systemic immune response targeting contralateral tumors and ultimately resulting in tumor regrowth. Mechanistically, we show that IRE augments IFN- γ signaling, resulting in the up-regulation of the PD-L1 checkpoint in pancreatic cancer cells. Together, these findings shed light on potential mechanisms of tumor regrowth following IRE treatment and offer insights into co-therapeutic targets to improve treatment strategies.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1352821/fulliretumor ablationimmunomodulationtumor recurrencecell cycle arresttumor microenvironment |
| spellingShingle | Khan Mohammad Imran Rebecca M. Brock Natalie Beitel-White Natalie Beitel-White Manali Powar Katie Orr Kenneth N. Aycock Nastaran Alinezhadbalalami Zaid S. Salameh Paige Eversole Benjamin Tintera Justin Markov Madanick Alissa Hendricks-Wenger Sheryl Coutermarsh-Ott Rafael V. Davalos Irving C. Allen Irving C. Allen Irving C. Allen Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer model Frontiers in Immunology ire tumor ablation immunomodulation tumor recurrence cell cycle arrest tumor microenvironment |
| title | Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer model |
| title_full | Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer model |
| title_fullStr | Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer model |
| title_full_unstemmed | Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer model |
| title_short | Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer model |
| title_sort | irreversible electroporation promotes a pro inflammatory tumor microenvironment and anti tumor immunity in a mouse pancreatic cancer model |
| topic | ire tumor ablation immunomodulation tumor recurrence cell cycle arrest tumor microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1352821/full |
| work_keys_str_mv | AT khanmohammadimran irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT rebeccambrock irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT nataliebeitelwhite irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT nataliebeitelwhite irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT manalipowar irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT katieorr irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT kennethnaycock irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT nastaranalinezhadbalalami irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT zaidssalameh irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT paigeeversole irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT benjamintintera irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT justinmarkovmadanick irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT alissahendrickswenger irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT sherylcoutermarshott irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT rafaelvdavalos irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT irvingcallen irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT irvingcallen irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel AT irvingcallen irreversibleelectroporationpromotesaproinflammatorytumormicroenvironmentandantitumorimmunityinamousepancreaticcancermodel |