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 and Yoji Shimizu ()
Additional contact information
Brandon J. Burbach: University of Minnesota
Stephen D. O’Flanagan: University of Minnesota
Qi Shao: University of Minnesota
Katharine M. Young: University of Minnesota
Joseph R. Slaughter: University of Minnesota
Meagan R. Rollins: University of Minnesota
Tami Jo L. Street: University of Minnesota
Victoria E. Granger: University of Minnesota
Lalit. K. Beura: University of Minnesota
Samira M. Azarin: University of Minnesota
Satish Ramadhyani: BTG plc
Bruce R. Forsyth: Boston Scientific Corporation
John C. Bischof: University of Minnesota
Yoji Shimizu: University of Minnesota

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24132-6

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