Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer.
Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer.
复制标题
DOI：
10.1158/0008-5472.can-20-1674
复制
发表时间：
2021-01-01
期刊：
影响因子：
11.2
通讯作者：
Hill SJ
中科院分区：
文献类型：
--
作者：
Wan C;Keany MP;Dong H;Al-Alem LF;Pandya UM;Lazo S;Boehnke K;Lynch KN;Xu R;Zarrella DT;Gu S;Cejas P;Lim K;Long HW;Elias KM;Horowitz NS;Feltmate CM;Muto MG;Worley MJ Jr;Berkowitz RS;Matulonis UA;Nucci MR;Crum CP;Rueda BR;Brown M;Liu XS;Hill SJ
免疫疗法在高级别浆液性卵巢癌（HGSC）中的疗效有限，因为这些药物在HGSC中的细胞靶点和作用机制尚不清楚。在这里，我们对用独特的双特异性抗PD-1/PD-L1抗体处理的新型HGSC类器官/免疫细胞共培养物进行了免疫功能和单细胞RNA-seq转录谱分析，与单特异性抗PD-1或抗PD-L1对照相比。通过真实的比较这些药物在所有免疫细胞类型中的功能，确定了目前无法获得的单特异性疗法的关键免疫检查点阻断（ICB）靶标。双特异性抗体在T细胞和NK细胞中诱导上级细胞状态变化。它独特地诱导NK细胞从惰性转变为更具活性和细胞毒性的表型，暗示NK细胞是HGSC中当前ICB诱导的免疫应答的关键缺失组分。它还诱导CD 8 T细胞亚群从幼稚转变为治疗后更具活性和细胞毒性祖细胞耗尽的表型，揭示了HGSC中对ICB应答的小的、先前未表征的CD 8 T细胞群体。这些状态变化部分通过双特异性抗体诱导的含溴结构域蛋白BRD 1的下调来驱动。BRD 1的小分子抑制在体外诱导了类似的状态变化，并在体内证明了功效，验证了共培养结果。我们的研究结果表明，NK细胞和T细胞亚群的状态变化可能是诱导有效的抗肿瘤免疫应答的关键，并表明能够诱导这种细胞状态变化的免疫疗法，如BRD 1抑制剂，可能在HGSC中具有增加的功效。
Immune therapies have had limited efficacy in high grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single cell RNA-seq transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-PD-1/PD-L1 antibody compared to monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and NK cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC.