Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling.
Lymphodepletion with total body irradiation (TBI) increases the efficacy of adoptively transferred tumor-specific CD8(+) T cells by depleting inhibitory lymphocytes and increasing homeostatic cytokine levels. We found that TBI augmented the function of adoptively transferred CD8(+) T cells in mice genetically deficient in all lymphocytes, indicating the existence of another TBI mechanism of action. Additional investigation revealed commensal gut microflora in the mesenteric lymph nodes and elevated LPS levels in the sera of irradiated mice. These findings correlated with increased dendritic cell activation and heightened levels of systemic inflammatory cytokines. Reduction of host microflora using antibiotics, neutralization of serum LPS using polymyxin B, or removal of LPS signaling components using mice genetically deficient in CD14 and TLR4 reduced the beneficial effects of TBI on tumor regression. Conversely, administration of microbial ligand-containing serum or ultrapure LPS from irradiated animals to nonirradiated antibody-lymphodepleted mice enhanced CD8(+) T cell activation and improved tumor regression. Administration of ultrapure LPS to irradiated animals further enhanced the number and function of the adoptively transferred cells, leading to long-term cure of mice with large B16F10 tumors and enhanced autoimmune vitiligo. Thus, disruption of the homeostatic balance between the host and microbes can enhance cell-based tumor immunotherapy.
National Cancer Institute (NCI), NIH, Bethesda, Maryland 20892-1502, USA.
Chrystal M
CM
Paulos
Claudia
C
Wrzesinski
Andrew
A
Kaiser
Christian S
CS
Hinrichs
Marcello
M
Chieppa
Lydie
L
Cassard
Douglas C
DC
Palmer
Andrea
A
Boni
Pawel
P
Muranski
Zhiya
Z
Yu
Luca
L
Gattinoni
Paul A
PA
Antony
Steven A
SA
Rosenberg
Nicholas P
NP
Restifo
D019264:Adoptive Transfer; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D018988:Bacterial Translocation / Q000276:immunology* / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000628:therapy; D011112:Polymyxin B / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014820:Vitiligo / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D014916:Whole-Body Irradiation
D000900:Anti-Bacterial Agents; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D011112:Polymyxin B