BRAFV600E-induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenografts
BRAFV600E-induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenografts
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DOI：
10.1038/s41388-019-0919-y
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发表时间：
2019-10-10
期刊：
影响因子：
8
通讯作者：
Sinicrope, Frank A.
中科院分区：
文献类型：
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作者：
Feng, Daofu;Qin, Bo;Sinicrope, Frank A.
程序性死亡配体1（PD-L1）是一种免疫检查点蛋白;然而，新出现的数据表明，肿瘤细胞PD-L1可能调节免疫非依赖性和内在细胞功能。我们证明了致癌BRAF（V600 E）对PD-L1的调节，并研究了其影响结直肠癌（CRC）细胞凋亡易感性的能力。与野生型BRAF相比，内源性或外源性突变体BRAF可增加PD-L1信使RNA（mRNA）和蛋白表达，MEK（促分裂原活化蛋白激酶/细胞外信号调节激酶）抑制或c-JUN和雅普敲低可减弱这种表达。PD-L1的缺失减少了体外和体内肿瘤细胞的生长。PD-L1的丢失也被证明可以减弱由多种抗癌药物诱导的DNA损伤和细胞凋亡，这些药物可以通过恢复野生型PD-L1而逆转，但不能通过缺失其胞外或胞内结构域的突变体逆转。PD-L1对化疗敏感性的影响在由PD-L1敲除与亲本细胞产生的MC 38小鼠肿瘤异种移植物中得到证实。PD-L1的缺失抑制了仅BH 3的BIM和BIK蛋白，这些蛋白可以通过PD-L1的重新表达而恢复; BIM的重新引入增强了细胞凋亡。PD-L1表达在BRAF（V600 E）人结肠癌中显著增加，肿瘤具有高PD-L1与低PD-L1的患者具有显著更好的生存期。总之，BRAF（V600 E）可转录上调PD-L1表达，这显示出诱导BIM和BIK以增强化疗诱导的细胞凋亡。这些数据表明PD-L1的内在非免疫功能，并表明肿瘤细胞PD-L1作为预测生物标志物的潜力。
Programmed death ligand 1 (PD-L1) is an immune checkpoint protein; however, emerging data suggest that tumor cell PD-L1 may regulate immune-independent and intrinsic cellular functions. We demonstrate regulation of PD-L1 by oncogenic BRAF(V600E) and investigated its ability to influence apoptotic susceptibility in colorectal cancer (CRC) cells. Endogenous or exogenous mutant vs. wild-type BRAF were shown to increase PD-L1 messenger RNA (mRNA) and protein expression that was attenuated by MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase) inhibition or c-JUN and YAP knockdown. Deletion of PD-L1 reduced tumor cell growth in vitro and in vivo. Loss of PD-L1 was also shown to attenuate DNA damage and apoptosis induced by diverse anti-cancer drugs that could be reversed by restoration of wild-type PD-L1, but not mutants with deletion of its extra- or intracellular domain. The effect of PD-L1 on chemosensitivity was confirmed in MC38 murine tumor xenografts generated from PD-L1-knockout vs. parental cells. Deletion of PD-L1 suppressed BH3-only BIM and BIK proteins that could be restored by re-expression of PD-L1; re-introduction of BIM enhanced apoptosis. PD-L1 expression was significantly increased in BRAF(V600E) human colon cancers, and patients whose tumors had high vs. low PD-L1 had significantly better survival. In summary, BRAF(V600E) can transcriptionally upregulate PD-L1 expression that was shown to induce BIM and BIK to enhance chemotherapy-induced apoptosis. These data indicate an intrinsic, non-immune function of PD-L1, and suggest the potential for tumor cell PD-L1 as a predictive biomarker.