Lipid accumulation and dendritic cell dysfunction in cancer.
Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.
Herber
Donna L
DL
Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA.
Cao
Wei
W
Nefedova
Yulia
Y
Novitskiy
Sergey V
SV
Nagaraj
Srinivas
S
Tyurin
Vladimir A
VA
Corzo
Alex
A
Cho
Hyun-Il
HI
Celis
Esteban
E
Lennox
Brianna
B
Knight
Stella C
SC
Padhya
Tapan
T
McCaffrey
Thomas V
TV
McCaffrey
Judith C
JC
Antonia
Scott
S
Fishman
Mayer
M
Ferris
Robert L
RL
Kagan
Valerian E
VE
Gabrilovich
Dmitry I
DI
D000818:Animals; D001896:Boron Compounds / Q000493:pharmacokinetics; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D005227:Fatty Acids / Q000032:analysis / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D014407:Tumor Cells, Cultured
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D005227:Fatty Acids; D005456:Fluorescent Dyes; C495140:Msr1 protein, mouse; D051117:Scavenger Receptors, Class A