STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer.
STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer.
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DOI：
10.1038/s41467-022-30568-1
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发表时间：
2022-05-31
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
PARP抑制剂（PARPi）已经彻底改变了BRCA突变晚期卵巢肿瘤的治疗前景。然而，这类抑制剂对晚期brca突变乳腺癌患者的影响相对较小。利用Brca1缺失驱动的乳腺肿瘤小鼠模型，我们发现肿瘤相关巨噬细胞（tam）在体内和体外都能减弱PARPi的功效。在机制上，brca1缺陷的乳腺肿瘤细胞诱导tam的肿瘤前极化，进而抑制parpi引发的肿瘤细胞DNA损伤，导致dsDNA片段的产生减少和合成致死性降低，从而损害sting依赖的抗肿瘤免疫。STING激动剂以巨噬细胞STING依赖的方式将m2样的促肿瘤巨噬细胞重编程为m1样的抗肿瘤状态。全身给药STING激动剂打破了肿瘤细胞介导的免疫细胞的多层抑制，并与PARPi协同抑制肿瘤生长。这种组合的治疗益处需要宿主STING，并由I型IFN反应和CD8+ T细胞介导，但不依赖于肿瘤细胞固有的STING。我们的数据说明了靶向先天免疫抑制促进parpi介导的乳腺癌抗肿瘤免疫参与的重要性。PARP抑制剂（PARPi）治疗在BRCA突变的晚期乳腺癌中仅显示出适度的疗效。作者发现，在brca1缺失的乳腺肿瘤细胞中，通过抑制PARPi引发的DNA损伤和减少dsDNA的产生，肿瘤相关巨噬细胞有助于PARPi的耐药，而这种耐药可以通过STING激动作用克服。
PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer. PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
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-19-1773
发表时间：
2020-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hutchinson KE;Yost SE;Chang CW;Johnson RM;Carr AR;McAdam PR;Halligan DL;Chang CC;Schmolze D;Liang J;Yuan Y
通讯作者：
Yuan Y
影响因子：
50.3
作者：
Kumar V;Donthireddy L;Marvel D;Condamine T;Wang F;Lavilla-Alonso S;Hashimoto A;Vonteddu P;Behera R;Goins MA;Mulligan C;Nam B;Hockstein N;Denstman F;Shakamuri S;Speicher DW;Weeraratna AT;Chao T;Vonderheide RH;Languino LR;Ordentlich P;Liu Q;Xu X;Lo A;Puré E;Zhang C;Loboda A;Sepulveda MA;Snyder LA;Gabrilovich DI
通讯作者：
Gabrilovich DI