Listeria delivers tetanus toxoid protein to pancreatic tumors and induces cancer cell death in mice

Benson Chellakkan Selvanesan, Dinesh Chandra, Wilber Quispe, Arthee Jahangir, Ankur Patel, Kiran Meena, Rodrigo Alberto Alves Da Silva, Madeline Friedman, Lisa Gabor, Olivia Khouri, Steven K. Libutti, Zi Qiang Yuan, Jenny Li, Sarah Siddiqui, Amanda Beck, Lydia Tesfa, Wade Koba, Jennifer Chuy, John C. McAuliffe, Rojin JafariDavid Entenberg, Yarong Wang, John Condeelis, Vera DesMarais, Vinod Balachandran, Xusheng Zhang, Ken Lin, Claudia Gravekamp

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease. Tumors are poorly immunogenic and immunosuppressive, preventing T cell activation in the tumor microenvironment. Here, we present a microbial-based immunotherapeutic treatment for selective delivery of an immunogenic tetanus toxoid protein (TT856-1313) into PDAC tumor cells by attenuated Listeria monocytogenes. This treatment reactivated preexisting TT-specific memory T cells to kill infected tumor cells in mice. Treatment of KrasG12D,p53R172H, Pdx1-Cre (KPC) mice with Listeria-TT resulted in TT accumulation inside tumor cells, attraction of TT-specific memory CD4 T cells to the tumor microenvironment, and production of perforin and granzyme B in tumors. Low doses of gemcitabine (GEM) increased immune effects of Listeria-TT, turning immunologically cold into hot tumors in mice. In vivo depletion of T cells from Listeria-TT + GEM-treated mice demonstrated a CD4 T cell-mediated reduction in tumor burden. CD4 T cells from TT-vaccinated mice were able to kill TT-expressing Panc-02 tumor cells in vitro. In addition, peritumoral lymph node-like structures were observed in close contact with pancreatic tumors in KPC mice treated with Listeria-TT or Listeria-TT + GEM. These structures displayed CD4 and CD8 T cells producing perforin and granzyme B. Whereas CD4 T cells efficiently infiltrated the KPC tumors, CD8 T cells did not. Listeria-TT + GEM treatment of KPC mice with advanced PDAC reduced tumor burden by 80% and metastases by 87% after treatment and increased survival by 40% compared to nontreated mice. These results suggest that Listeria-delivered recall antigens could be an alternative to neoantigen-mediated cancer immunotherapy.

Original languageEnglish (US)
Article numbereabc1600
JournalScience translational medicine
Volume14
Issue number637
DOIs
StatePublished - Mar 23 2022

ASJC Scopus subject areas

  • Medicine(all)

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