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Induction of Immunogenic Cell Death with Non-Thermal Plasma for Cancer Immunotherapy
Start Date: 5/5/2017Start Time: 2:00 PM
End Date: 5/5/2017End Time: 4:00 PM

Event Description
BIOMED PhD Thesis Defense

Title:
Induction of Immunogenic Cell Death with Non-Thermal Plasma for Cancer Immunotherapy

Speaker:
Abraham Lin, PhD Candidate, School of Biomedical Engineering, Science and Health Systems

Advisors:
Vandana Miller, MD, Director, Plasma Medicine Laboratory and Associate Research Professor, C. & J. Nyheim Plasma Institute

Ken Barbee, PhD, Professor, Senior Associate Dean, and Associate Dean for Research, School of Biomedical Engineering, Science and Health Systems

Abstract:
Even with the recent advancements in cancer immunotherapy, treatments are still associated with debilitating side effects and unacceptable fail rates. Induction of immunogenic cell death (ICD) in tumors is a promising approach to cancer treatment that may overcome these deficiencies. Cells undergoing ICD pathways enhance the interactions between cancerous cells and immune cells of the patient, resulting in the generation of anti-cancer immunity. The goal of this therapy relies on the engagement and reestablishment of the patient’s natural immune processes to target and eliminate cancerous cells systemically.

The main objective of this research was to determine if non-thermal plasma could be used to elicit immunogenic cancer cell death for cancer immunotherapy. My hypothesis was that plasma induces immunogenic cancer cell death through oxidative stress pathways, followed by development of a specific anti-tumor immune response. This was test by investigating the interactions between plasma and multiple cancerous cells in vitro and validating anti-tumor immune responses in vivo. Following plasma treatment, two surrogate ICD markers, secreted adenosine triphosphate (ATP) and surface exposed calreticulin (ecto-CRT), were emitted from all three cancerous cell lines tested: A549 lung carcinoma cell line, CNE-1 radiation-resistant nasopharyngeal cell line and CT26 colorectal cancer cell line. When these cells were co-cultured with macrophages, cells of the innate immune system, the tumoricidal activity of macrophages was enhanced, thus demonstrating the immunostimulatory activity of cells undergoing ICD.

The underlying mechanisms of plasma-induced ICD were also evaluated. When plasma is generated, four major components are produced including electromagnetic fields, ultraviolet radiation, and charged and neutral reactive species. Of these, we determined that plasma-generated charged and short-lived reactive oxygen species (ROS) were the major effectors of ICD. Following plasma treatment, ROS immediately increased, up to four hours, before decreasing at 24 hours. When chemical attenuators of ROS were used, intracellular ROS was abrogated and emission of ICD markers were attenuated. This strongly suggests that plasma-induced ICD is associated with increased intracellular ROS.

The gold-standard approach to evaluating whether a stimulus can elicit genuine ICD relies on a vaccination assay. CT26 colorectal cancer cells were treated at ICD-inducing regimes of plasma and injected into syngeneic Balb/c mice. One week later, mice were challenged with live CT26 cancer cells. Tumor progression was moderated in animals immunized with plasma-treated CT26 cells. Altogether, these provide strong evidence that plasma regimes can be adapted for a new application: ICD induction. Next, a study was conducted to test the potential of plasma to induce ICD in tumors in animals. Plasma treatment of subcutaneous tumors in mice elicited the emission of CRT and high mobility group box 1 (HMGB1), another maker of ICD, in the tumor and also recruited CD11c+ and CD45+ immune cells locally. This was followed by cancer-specific splenic T cell development that was significantly more than in controls (<0.05), indicating that a systemic anti-tumor response was elicited from localized plasma treatment of the tumor.

Overall, this work demonstrates the development of non-thermal plasma as a novel method of inducing immunogenic cell death for cancer immunotherapy. The obtained results further our understanding of plasma-cellular interaction mechanisms and highlight the potential for clinical translation.
Contact Information:
Name: Ken Barbee
Phone: 215-895-1335
Email: barbee@drexel.edu
Abraham Lin
Location:
Bossone Research Center, Room 709, located at 32nd and Market Streets.
Audience:
  • Undergraduate Students
  • Graduate Students
  • Faculty
  • Staff

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