Irreversible electroporation augments checkpoint immunotherapy in prostate cancer and promotes tumor antigen-specific tissue-resident memory CD8+ T cells

Brandon J. Burbach, Stephen D. O’Flanagan, Qi Shao, Katharine M. Young, Joseph R. Slaughter, Meagan R. Rollins, Tami Jo L. Street, Victoria E. Granger, Lalit K. Beura, Samira M. Azarin, Satish Ramadhyani, Bruce R. Forsyth, John C. Bischof, Yoji Shimizu

Research output: Contribution to journalArticlepeer-review

Abstract

Memory CD8+ T cells populate non-lymphoid tissues (NLTs) following pathogen infection, but little is known about the establishment of endogenous tumor-specific tissue-resident memory T cells (TRM) during cancer immunotherapy. Using a transplantable mouse model of prostate carcinoma, here we report that tumor challenge leads to expansion of naïve neoantigen-specific CD8+ T cells and formation of a small population of non-recirculating TRM in several NLTs. Primary tumor destruction by irreversible electroporation (IRE), followed by anti-CTLA-4 immune checkpoint inhibitor (ICI), promotes robust expansion of tumor-specific CD8+ T cells in blood, tumor, and NLTs. Parabiosis studies confirm that TRM establishment following dual therapy is associated with tumor remission in a subset of cases and protection from subsequent tumor challenge. Addition of anti-PD-1 following dual IRE + anti-CTLA-4 treatment blocks tumor growth in non-responsive cases. This work indicates that focal tumor destruction using IRE combined with ICI is a potent in situ tumor vaccination strategy that generates protective tumor-specific TRM.

Original languageEnglish (US)
Article number3862
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Jun 23 2021

Bibliographical note

Funding Information:
The NIH Tetramer Core (Emory University) provided SPAS-1 loaded H2-Db MHC-I tetramers used for preliminary experiments. We thank Drs. Sathi Wijeyesinghe and Andrew Soerens for technical assistance with surgery and production of H2-Db MHC-I SPAS-1 monomers, respectively. Drs. Vaiva Vezys, Scott Dehm, Charles Ryan, and Paolo Provenzano from the University of Minnesota provided helpful critical discussion. LKB is a Searle Scholar. This work was funded by a seed grant from the University of Minnesota Institute for Engineering in Medicine, discovery funds from Boston Scientific Corporation (Maple Grove, MN), discovery funds from BTG plc. (Farnham, United Kingdom), Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., and NIH R21 AI123600. We thank Therese Martin and the University of Minnesota Cancer Center Flow Cytometry Resource (UFCR) for technical assistance with flow cytometry applications. The University of Minnesota Masonic Cancer Center is supported by NIH P30 CA77598.

Publisher Copyright:
© 2021, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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