Engineering T cell response to cancer antigens by choice of focal therapeutic conditions

Qi Shao, Stephen O'Flanagan, Tiffany Lam, Priyatanu Roy, Francisco Pelaez, Brandon J. Burbach, Samira M. Azarin, Yoji Shimizu, John C. Bischof

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Focal thermal therapy (Heat), cryosurgery (Cryo) and irreversible electroporation (IRE) are increasingly used to treat cancer. However, local recurrence and systemic spread are persistent negative outcomes. Nevertheless, emerging work with immunotherapies (i.e., checkpoint blockade or dendritic cell (DC) vaccination) in concert with focal therapies may improve outcomes. To understand the role of focal therapy in priming the immune system for immunotherapy, an in vitro model of T cell response after exposure to B16 melanoma cell lysates after lethal exposures was designed. Exposure included: Heat (50 °C, 30 min), Cryo (−80 °C, 30 min) and IRE (1250 V/cm, 99 pulses, 50 µs pulses with 1 Hz intervals). After viability assessment (CCK-8 assay), cell lysates were collected and assessed for protein release (BCA assay), protein denaturation (FTIR-spectroscopy), TRP-2 antigen release (western blot), and T cell activation (antigen-specific CD8 T cell proliferation). Results showed IRE released the most protein and antigen (TRP-2), followed by Cryo and Heat. In contrast, Cryo released the most native (not denatured) protein, compared to IRE and Heat. Finally, IRE dramatically outperformed both Cryo and Heat in T cell activation while Cryo modestly outperformed Heat. This study demonstrates that despite all focal therapies ability to destroy cells, the ‘quantity’ (i.e., amount) and ‘quality’ (i.e., molecular state) of tumor protein (including antigen) released can dramatically change the ensuing priming of the immune system. This suggests protein-based metrics whereby focal therapies can be designed to prime the immune system in concert with immunotherapies to eventually achieve improved and durable cancer treatment in vivo.

Original languageEnglish (US)
Pages (from-to)130-138
Number of pages9
JournalInternational Journal of Hyperthermia
Volume36
Issue number1
DOIs
StatePublished - Jan 1 2019

Bibliographical note

Funding Information:
This study was supported by Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee, Boston Scientific Corporation, the Institute for Engineering in Medicine (University of Minnesota) and BTG plc. JCB was also supported by the Carl and Janet Kuhrmeyer Chair in the Department of Mechanical Engineering We thank Jackson Raynor and Feng Liu for technical support.

Publisher Copyright:
© 2019, © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.

Keywords

  • B16
  • CD8 T cell
  • Focal therapy
  • T cell activation
  • antigen
  • antigen presenting cells
  • cancer
  • dendritic cells
  • immune response
  • melanoma
  • proliferation
  • protein denaturation
  • protein release
  • viability
  • western blot

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