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

doi:10.1038/s41467-021-24132-6

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

Nat Commun. 2021 Jun 23;12(1):3862. doi: 10.1038/s41467-021-24132-6.

Authors

Brandon J Burbach^#^{1

2

3

4}, Stephen D O'Flanagan^#^{5

6

7}, Qi Shao^#^{8

9

10}, Katharine M Young^{5

6}, Joseph R Slaughter^{5

6}, Meagan R Rollins^{5

6

11}, Tami Jo L Street^{5

6}, Victoria E Granger^{5

6}, Lalit K Beura^{6

7

12}, Samira M Azarin^{8

9

13}, Satish Ramadhyani¹⁴, Bruce R Forsyth¹¹, John C Bischof^{8

9

10

15}, Yoji Shimizu^{16

17

18

19}

Affiliations

¹ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. burba005@umn.edu.
² Center for Immunology, University of Minnesota, Minneapolis, USA. burba005@umn.edu.
³ Masonic Cancer Center, University of Minnesota, Minneapolis, USA. burba005@umn.edu.
⁴ Institute for Engineering in Medicine, University of Minnesota, Minneapolis, USA. burba005@umn.edu.
⁵ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁶ Center for Immunology, University of Minnesota, Minneapolis, USA.
⁷ Department of Microbiology and Immunology, University of Minnesota, Minneapolis, USA.
⁸ Masonic Cancer Center, University of Minnesota, Minneapolis, USA.
⁹ Institute for Engineering in Medicine, University of Minnesota, Minneapolis, USA.
¹⁰ Department of Mechanical Engineering, University of Minnesota, Minneapolis, USA.
¹¹ Boston Scientific Corporation, Maple Grove, MN, USA.
¹² Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.
¹³ Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, USA.
¹⁴ BTG plc, Arden Hills, MN, USA.
¹⁵ Department of Biomedical Engineering, University of Minnesota, Minneapolis, USA.
¹⁶ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. shimi002@umn.edu.
¹⁷ Center for Immunology, University of Minnesota, Minneapolis, USA. shimi002@umn.edu.
¹⁸ Masonic Cancer Center, University of Minnesota, Minneapolis, USA. shimi002@umn.edu.
¹⁹ Institute for Engineering in Medicine, University of Minnesota, Minneapolis, USA. shimi002@umn.edu.

^# Contributed equally.

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 (T_RM) 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 T_RM 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 T_RM 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 T_RM.

Publication types

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

MeSH terms

Animals
Antigens, Neoplasm / immunology
Antigens, Neoplasm / metabolism
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
Cell Line, Tumor
Disease Models, Animal
Electroporation / methods*
Humans
Immune Checkpoint Inhibitors / pharmacology*
Immunologic Memory / immunology
Immunotherapy / methods*
Kaplan-Meier Estimate
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Prostatic Neoplasms / immunology
Prostatic Neoplasms / therapy*
Tumor Microenvironment / immunology

Substances

Antigens, Neoplasm
Immune Checkpoint Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding