TY - JOUR
T1 - Listeria delivers tetanus toxoid protein to pancreatic tumors and induces cancer cell death in mice
AU - Selvanesan, Benson Chellakkan
AU - Chandra, Dinesh
AU - Quispe-Tintaya, Wilber
AU - Jahangir, Arthee
AU - Patel, Ankur
AU - Meena, Kiran
AU - Da Silva, Rodrigo Alberto Alves
AU - Friedman, Madeline
AU - Gabor, Lisa
AU - Khouri, Olivia
AU - Libutti, Steven K.
AU - Yuan, Ziqiang
AU - Li, Jenny
AU - Siddiqui, Sarah
AU - Beck, Amanda
AU - Tesfa, Lydia
AU - Koba, Wade
AU - Chuy, Jennifer
AU - McAuliffe, John C.
AU - Jafari, Rojin
AU - Entenberg, David
AU - Wang, Yarong
AU - Condeelis, John
AU - DesMarais, Vera
AU - Balachandran, Vinod
AU - Zhang, Xusheng
AU - Lin, Ken
AU - Gravekamp, Claudia
N1 - Publisher Copyright: Copyright © 2022 The Authors
PY - 2022/3/23
Y1 - 2022/3/23
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85126860168
UR - https://www.scopus.com/pages/publications/85126860168#tab=citedBy
U2 - 10.1126/scitranslmed.abc1600
DO - 10.1126/scitranslmed.abc1600
M3 - Article
C2 - 35320003
SN - 1946-6234
VL - 14
JO - Science translational medicine
JF - Science translational medicine
IS - 637
M1 - eabc1600
ER -