STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer.
STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer.
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DOI：
10.1136/jitc-2022-005627
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发表时间：
2023-01
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）已在BRCA突变卵巢癌患者中显示出有效的治疗效果。然而，对PARPi的获得性耐药性仍然是临床上的主要挑战。PARPi耐药卵巢癌小鼠模型通过奥拉帕尼在同基因Brca 1缺陷卵巢肿瘤中的长期治疗产生。在体外通过共培养实验和在体内通过分析人和小鼠PARPi抗性肿瘤的肿瘤微环境（TME）中的免疫细胞来研究信号转导子和转录激活子3（STAT 3）介导的免疫抑制。进行全基因组转录组分析以评估STING（干扰素基因刺激剂）激动剂对PARPi抗性卵巢肿瘤的TME中的骨髓细胞的抗肿瘤免疫调节作用。STING激动剂用于克服卵巢癌的同基因和患者来源的异种移植物模型中STAT 3介导的免疫抑制和获得性PARPi抗性。在这项研究中，我们发现了一个适应性耐药机制，PARP抑制介导的肿瘤相关的巨噬细胞（TAMs）在TME。在BRCA缺陷卵巢肿瘤中发现了显著增加的促肿瘤巨噬细胞群体，其在小鼠模型和患者中均对PARPi产生抗性。从机制上讲，PARP抑制提高了肿瘤细胞中的STAT 3信号通路，这反过来又促进了TAM的促肿瘤极化。肿瘤细胞中的STAT 3消融减轻了前肿瘤巨噬细胞的极化，并增加了肿瘤浸润T细胞对PARP抑制的作用。这些发现在患者来源的PARPi耐药BRCA 1突变卵巢肿瘤中得到证实。重要的是，STING激动剂通过重编程骨髓细胞重塑免疫抑制性TME，并克服卵巢癌中对PARPi的TME依赖性适应性抗性。这种作用通过加入程序性细胞死亡蛋白-1阻断剂进一步增强。我们阐明了BRCA 1突变卵巢肿瘤中对PARPi产生耐药性的适应性免疫抑制机制。这是由肿瘤细胞中PARPi诱导的STAT 3激活所推动的促肿瘤TAM的富集介导的。我们还提供了一种新的策略，用STING激动剂重塑免疫抑制性TME，并克服卵巢癌中的PARPi耐药性。
Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic. PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer. In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade. We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.
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影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1158/1078-0432.ccr-16-1237
发表时间：
2017-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Liu JF;Palakurthi S;Zeng Q;Zhou S;Ivanova E;Huang W;Zervantonakis IK;Selfors LM;Shen Y;Pritchard CC;Zheng M;Adleff V;Papp E;Piao H;Novak M;Fotheringham S;Wulf GM;English J;Kirschmeier PT;Velculescu VE;Paweletz C;Mills GB;Livingston DM;Brugge JS;Matulonis UA;Drapkin R
通讯作者：
Drapkin R
DOI：
10.1158/1078-0432.ccr-16-3215
发表时间：
2017-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jiao S;Xia W;Yamaguchi H;Wei Y;Chen MK;Hsu JM;Hsu JL;Yu WH;Du Y;Lee HH;Li CW;Chou CK;Lim SO;Chang SS;Litton J;Arun B;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
15.9
作者：
Chabanon, Roman M.;Muirhead, Gareth;Postel-Vinay, Sophie
通讯作者：
Postel-Vinay, Sophie
影响因子：
3.8
作者：
D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.