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

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.

• Authors: Benson Chellakkan Selvanesan, Dinesh Chandra, Wilber Quispe-Tintaya, Arthee Jahangir, Ankur Patel, Kiran Meena, Rodrigo Alberto Alves Da Silva, Madeline Friedman, Lisa Gabor, Olivia Khouri, Steven K Libutti, Ziqiang Yuan, Jenny Li, Sarah Siddiqui, Amanda Beck, Lydia Tesfa, Wade Koba, Jennifer Chuy, John C McAuliffe, Rojin Jafari, David Entenberg, Yarong Wang, John Condeelis, Vera DesMarais, Vinod Balachandran, Xusheng Zhang, Ken Lin, Claudia Gravekamp
• Journal: Science translational medicine (Sci Transl Med) Vol. 14 Issue 637 Pg. eabc1600 (03 23 2022) ISSN: 1946-6242 [Electronic] United States
• PMID: 35320003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tetanus Toxoid

Topics

• Animals
• Carcinoma, Pancreatic Ductal (pathology)
• Cell Death
• Disease Models, Animal
• Listeria
• Mice
• Pancreatic Neoplasms (drug therapy)
• Tetanus Toxoid (therapeutic use)
• Tumor Microenvironment