Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells.
Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells.
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DOI：
10.1073/pnas.2300706120
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发表时间：
2023-05-09
影响因子：
11.1
通讯作者：
Shalapour S
中科院分区：
文献类型：
--
作者：
Gu L;Zhu Y;Lee M;Nguyen A;Ryujin NT;Huang JY;Pandit SK;Chamseddine S;Xiao L;Mohamed YI;Kaseb AO;Karin M;Shalapour S
免疫检查点抑制剂用于HCC治疗，但单药PD-1/PD-L1阻滞剂的总体反应率仍然很低。使用NASH驱动的HCC小鼠模型，我们表明，与安全和廉价的血管紧张素II受体抑制剂氯沙坦共同治疗显著增强了抗PD-1触发的HCC消退。虽然氯沙坦没有增强耗尽的CD 8 + T细胞的复苏，但它大大增强了它们的肿瘤内侵袭，我们推测这是由肿瘤周围纤维化损害的。事实上，氯沙坦的有益作用与TGF-β信号传导和胶原沉积的抑制以及免疫抑制性成纤维细胞的消耗相关。应评估氯沙坦在接受PD-1/PD-L1阻断治疗的HCC患者中的辅助活性。虽然病毒性肝细胞癌（HCC）正在下降，但非病毒性HCC，通常是非酒精性或酒精性脂肪性肝炎（NASH，ASH）的终末期，正处于上升趋势。阻断T细胞抑制性受体PD-1的免疫检查点抑制剂（ICI）已被批准用于治疗所有类型的HCC。然而，只有少数HCC患者对PD-1阻断表现出稳健和持续的反应，这需要更好地了解对反应率和持续时间产生负面影响的因素，并发现可增强ICI反应性的新辅助治疗。使用NASH驱动的HCC小鼠模型，我们确定瘤周纤维化是T细胞介导的肿瘤消退的潜在障碍，并假设抗纤维化药物可能增加ICI反应性。我们现在表明，血管紧张素II受体抑制剂氯沙坦，一种常用的处方和安全的抗高血压药物，减少肝脏和肿瘤周围纤维化，并大大增强抗PD-1诱导的肿瘤消退。虽然氯沙坦没有增强T细胞的复苏，但与单独的PD-1阻断相比，它显著增强了效应CD 8 + T细胞对HCC的浸润。氯沙坦的有益作用与减弱TGF-β受体信号传导、减少胶原沉积和消耗免疫抑制性成纤维细胞相关。
Immune checkpoint inhibitors are used in HCC treatment, but overall response rates for single-agent PD-1/PD-L1 blockers have remained stubbornly low. Using a mouse model of NASH-driven HCC, we show that cotreatment with the safe and inexpensive angiotensin II receptor inhibitor losartan substantially enhanced anti-PD-1-triggered HCC regression. Although losartan did not potentiate the reinvigoration of exhausted CD8+ T cells, it considerably enhanced their intratumoral invasion, which we postulated to be compromised by peritumoral fibrosis. Indeed, the beneficial effect of losartan correlated with inhibition of TGF-β signaling and collagen deposition, and depletion of immunosuppressive fibroblasts. Losartan should be evaluated for its adjuvant activity in HCC patients undergoing PD-1/PD-L1 blocking therapy. Although viral hepatocellular carcinoma (HCC) is declining, nonviral HCC, which often is the end stage of nonalcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICIs) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a minority of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell–mediated tumor regression and postulated that antifibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1-induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8+ T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with blunted TGF-β receptor signaling, reduced collagen deposition, and depletion of immunosuppressive fibroblasts.
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影响因子：
50.3
作者：
Nakagawa H;Umemura A;Taniguchi K;Font-Burgada J;Dhar D;Ogata H;Zhong Z;Valasek MA;Seki E;Hidalgo J;Koike K;Kaufman RJ;Karin M
通讯作者：
Karin M
DOI：
10.1158/1078-0432.ccr-21-1258
发表时间：
2023-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
通讯作者：
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DOI：
10.1073/pnas.2219199120
发表时间：
2023-02-07
影响因子：
11.1
作者：
Datta, Meenal;Chatterjee, Sampurna;Perez, Elizabeth M.;Gritsch, Simon;Roberge, Sylvie;Duquette, Mark;Chen, Ivy X.;Naxerova, Kamila;Kumar, Ashwin S.;Ghosh, Mitraji;Emblem, Kyrre E.;Ng, Mei R.;Ho, Willia W.;Kumar, Pragya;Krsihnan, Shanmugaraja;Dong, Xinyu;Speranza, Maria C.;Neagu, Martha R.;Iorgulescu, Bryan;Huang, Raymond Y.;Youssef, Gilbert;Reardon, David A.;Sharpe, Arlene H.;Freeman, Gordon J.;Suva, Mario L.;Xu, Lei;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
全球和区域血管紧张素II型1A受体失活对TGFBR1（M318R/+）小鼠的改善的不同贡献。
影响因子：
3.6
作者：
Bramel, Emily E.;Bagirzadeh, Rustam;Saqib, Muzna;Creamer, Tyler J.;Espinoza Camejo, Wendy A.;Roker, LaToya Ann;Pardo Habashi, Jennifer;Dietz, Harry C.;Gallo MacFarlane, Elena
通讯作者：
Gallo MacFarlane, Elena
影响因子：
4.7
作者：
Ehanire, Tosan;Ren, Licheng;Bond, Jennifer;Medina, Manuel;Li, George;Bashirov, Latif;Chen, Lei;Kokosis, George;Ibrahim, Mohamed;Selim, Angelica;Blobe, Gerard C.;Levinson, Howard
通讯作者：
Levinson, Howard