Blockade of Arf1-mediated lipid metabolism in cancers promotes tumor infiltration of cytotoxic T cells via the LPE-PPARγ-NF-κB-CCL5 pathway  

作　　者：Na Wang Tiange Yao Chenfei Luo Ling Sun Yuetong Wang Steven X.Hou 

机构地区：[1]Department of Cell and Developmental Biology at School of Life Sciences,State Key Laboratory of Genetic Engineering,Institute of Metabolism and Integrative Biology,Human Phenome Institute,Fudan University,Shanghai 200438,China

出　　处：《Life Metabolism》2023年第5期25-37,共13页生命（代谢（英文）

基　　金：This work was financially supported by grants from the National Natural Science Foundation of China(NSFC:92057205 and 32150710518 to S.X.H.,and 82203511 to Y.W.);Greater Bay Area Institute of Precision Medicine(Guangzhou),Fudan University,China.

摘　　要：Tumor immunotherapy has achieved breakthroughs in a variety of tumors. However, the systemic absence of T cells in tumors and immunosuppressive tumor microenvironment so far limits the efficacy of immunotherapy to a small population of patients. Therefore, novel agents to increase T-cell tumor infiltration are urgently needed in the clinic. We recently found that inhibition of the ADP-ribosylation factor 1 (Arf1)-mediated lipid metabolism not only kills cancer stem cells (CSCs) but also elicits an anti-tumor immune response. In this study, we revealed a mechanism that targeting Arf1 promotes the infiltration of cytotoxic T lymphocytes (CTLs) into tumors through the C-C chemokine ligand 5 (CCL5)- C-C chemokine receptor type 5 (CCR5) pathway. We found that blockage of Arf1 induces the production of the unsaturated fatty acid (PE 18:1) that binds and sequestrates peroxisome proliferator- activated receptor-γ (PPARγ) from the PPARγ-nuclear factor-κB (NF-κB) cytoplasmic complex. The released NF-κB was then phospho-rylated and translocated into the nucleus to regulate the transcription of chemokine CCL5. CCL5 promoted infiltration of CTLs for tumor regression. Furthermore, the combination of the Arf1 inhibitor and programmed cell death protein 1 (PD-1) blockade induced an even stronger anti-tumor immunity. Therefore, targeting Arf1 represents a novel anti-tumor immune approach by provoking T-cell tumor infiltration and may provide a new strategy for tumor immunotherapy.

关 键 词：immune checkpoint blockade cancer stem cells cytotoxic T cells PPARΓ CCL5-CCR5 pathway Arf1 

分 类 号：R730.2[医药卫生—肿瘤]