NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors.
NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors.
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DOI：
10.1158/0008-5472.can-19-3158
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发表时间：
2020-05-01
期刊：
影响因子：
11.2
通讯作者：
Thomas GJ
中科院分区：
文献类型：
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作者：
Ford K;Hanley CJ;Mellone M;Szyndralewiez C;Heitz F;Wiesel P;Wood O;Machado M;Lopez MA;Ganesan AP;Wang C;Chakravarthy A;Fenton TR;King EV;Vijayanand P;Ottensmeier CH;Al-Shamkhani A;Savelyeva N;Thomas GJ
Determining mechanisms of resistance to aPD-1/PD-L1 immune checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, there are no CAF-specific inhibitors clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, 4T1) to investigate how CAF influence the immune microenvironment and affect response to different immunotherapy modalities (anti-cancer vaccination; TC1, [HPV E7 DNA vaccine]; aPD-1, MC38) and found that CAFs broadly suppressed response by specifically excluding CD8+ T-cells from tumors (not CD4+ T-cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T-cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a non-depleting antibody overcame the CD8+ T-cell exclusion effect without affecting T-regs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this to TGF-b1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacological inhibition (GKT137831 [Setanaxib]) of NOX4 ‘normalized’ CAF to a quiescent phenotype and promoted intratumoral CD8+T-cell infiltration, overcoming the exclusion effect; TGF-b1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition, and could improve outcome in a broad range of cancers.
