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

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

doi:10.1038/s41467-021-24132-6

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.

Highlights

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
Two subsets of recirculating memory CD8+ T cells known as central memory (TCM) and effector memory (TEM) can be sampled in the blood but a third, non-recirculating subset known as tissue-resident memory (TRM) is parked in NLTs, and is of increasing interest for its role in both pathogen immunity and cancer immunotherapy[5,6,7,8]
We used the transplantable TRAMP-C2 prostate carcinoma cell model, as the rate of tumor growth is slow enough to allow for investigation of memory CD8+ T cells several weeks following tumor inoculation, and the tumors are known to be responsive to immune checkpoint inhibitor (ICI) treatment[35]

Summary

Results

Quantification of SPAS-1 specific T cell expansion. To aid in monitoring systemic immune responses to cancer immunotherapy, we first characterized the endogenous CD8+ T cell response to syngeneic TRAMP-C2 tumor injected subcutaneously into C57BL/6 mice. Tumor growth was detected ~2 weeks after

28 Peptide

Discussion

Methods