Listeria delivers tetanus toxoid protein to pancreatic tumors and induces cancer cell death in mice Journal Article
| Authors: | Selvanesan, B. C.; Chandra, D.; Quispe-Tintaya, W.; Jahangir, A.; Patel, A.; Meena, K.; Da Silva, R. A. A.; Friedman, M.; Gabor, L.; Khouri, O.; Libutti, S. K.; Yuan, Z.; Li, J.; Siddiqui, S.; Beck, A.; Tesfa, L.; Koba, W.; Chuy, J.; McAuliffe, J. C.; Jafari, R.; Entenberg, D.; Wang, Y.; Condeelis, J.; DesMarais, V.; Balachandran, V.; Zhang, X.; Lin, K.; Gravekamp, C. |
| Article Title: | 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. Copyright © 2022 The Authors |
| Keywords: | controlled study; survival rate; unclassified drug; human cell; nonhuman; gemcitabine; pancreatic neoplasms; drug megadose; cd8+ t lymphocyte; animal cell; mouse; animal; animals; mice; animal tissue; cell death; cancer immunotherapy; low drug dose; transforming growth factor beta; interleukin 10; carcinoma, pancreatic ductal; animal experiment; animal model; tumor regression; pathology; tumor antigen; pancreas carcinoma; disease model; liver metastasis; granzyme b; gamma interferon; myc protein; breast tumor; lymph node; pancreas tumor; cd4+ t lymphocyte; interleukin 6; single drug dose; pancreas adenocarcinoma; perforin; disease models, animal; t cell depletion; listeria monocytogenes; tetanus toxoid; memory t lymphocyte; tumor microenvironment; tumor-associated macrophage; pancreas metastasis; metastasis inhibition; interferon production; listeriolysin o; human; male; female; article; listeria; apoptosis rate; myeloid-derived suppressor cell; mia paca-2 cell line; panc02 cell line; tetanus toxoid protein[856-1313]; peritumoral lymph node |
| Journal Title: | Science Translational Medicine |
| Volume: | 14 |
| Issue: | 637 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2022-03-23 |
| Start Page: | eabc1600 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.abc1600 |
| PUBMED: | 35320003 |
| PROVIDER: | scopus |
| PMCID: | PMC9031812 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2022 -- Source: Scopus |
