Selective targeting of antitumor immune responses with engineered live-attenuated Listeria monocytogenes.
Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes.
Yoshimura
Kiyoshi
K
Immunology and Hematopoiesis Division, Department of Medical Oncology, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, MD 21231, USA.
Jain
Ajay
A
Allen
Heather E
HE
Laird
Lindsay S
LS
Chia
Christina Y
CY
Ravi
Sowmya
S
Brockstedt
Dirk G
DG
Giedlin
Martin A
MA
Bahjat
Keith S
KS
Leong
Meredith L
ML
Slansky
Jill E
JE
Cook
David N
DN
Dubensky
Thomas W
TW
Pardoll
Drew M
DM
Schulick
Richard D
RD
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D005818:Genetic Engineering; D006505:Hepatitis / Q000821:virology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007249:Inflammation; D008089:Listeria monocytogenes / Q000235:genetics* / Q000472:pathogenicity; D008113:Liver Neoplasms / Q000556:secondary / Q000628:therapy*; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes
D019496:Cancer Vaccines