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Enhancing CD8 T Cell Fatty Acid Catabolism within?a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy.

Cancer Cell. 2017; 
Zhang Ying,Kurupati Raj,Liu Ling,Zhou Xiang Yang,Zhang Gao,Hudaihed Abeer,Filisio Flavia,Giles-Davis Wynetta,Xu Xiaowei,Karakousis Giorgos C,Schuchter Lynn M,Xu Wei,Amaravadi Ravi,Xiao Min,Sadek Norah,Krepler Clemens,Herlyn Meenhard,Freeman Gordon J,Rabinowitz Joshua D,Ertl Hildegund
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Proteins, Expression, Isolation and Analysis For intracellular cytokine staining (ICS) of ex vivo stimulated lymphocytes, 106 cells per samples were cultured in DMEM containing 2% FBS and Golgiplug (Fisher Scientific, 1.5 ml/ml) for 6 hr with either a peptide pool (5 ug/ml for each peptide) including all CD8+ T cell epitopes expressed by gDMelapoly (mTrp-1455-463: TAPDNLGYA, mTrp-1481-489: IAVVAALLL, mTrp-2522-529: YAEDYEEL, hTp-2180-188: SVYDFFVWL, hTrp-2343-357: STFSFRNAL, mTrp-2363-371: SQVMNLHNL, hgp10025-33: KVPRNQDWL, mBraf 594-602: FGLANEKSI); the E7 peptide: RAHYNIVTTF or SIINFEKL peptide (all from Genscript) or a rabies virus glycoprotein control peptide. Get A Quote

摘要

How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8 TILs enhance peroxisome proliferator-activated receptor (PPAR)-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8 TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8 TILs' antigen specificity. Further promoting FA catabolism improves the CD8 TILs' ability to slow tumor progression. PD-1... More

关键词

CD8(+) T?cells,HIF-1α,TILs,co-inhibitors,fatty acid catabolism,fenofibrate,hypoglycemia,hypoxia,melanoma,tumor microenviron