Panobinostat Induced Spatial In Situ Biomarkers Predictive of Anti-PD-1 Efficacy in Mouse Mammary Carcinoma.
Panobinostat Induced Spatial In Situ Biomarkers Predictive of Anti-PD-1 Efficacy in Mouse Mammary Carcinoma.
复制标题
PanobinOstat诱导了小鼠乳腺癌中抗PD-1功效的空间原位生物标志物。
作者：
免疫疗法，包括抗PD-1免疫检查点阻断（ICB）抗体，已经彻底改变了许多实体恶性肿瘤的治疗。然而，它们在乳腺癌中的疗效仅限于一部分三阴性乳腺癌患者，其中ICB通常与一系列细胞毒性和靶向药物联合使用。预测乳腺癌对ICB治疗反应的可靠生物标志物严重缺失，尽管联合反应与免疫原性细胞死亡（ICD）相关。在这里，我们利用了最近开发的综合分析平台，多重植入式微器件检测（米马），以评估存在和空间细胞关系的文献为基础的候选标志物预测ICB的疗效在管腔小鼠乳腺癌。米马整合了（i）用于在肿瘤床内局部递送少量药物的可植入微型装置与（ii）顺序多重免疫组织化学（mIHC）和空间细胞分析管道，以快速（在几天内）描述药物作用机制并在复杂肿瘤组织中找到预测性生物标志物。我们发现，裂解的半胱天冬酶-3，ICAM-1，神经纤毛蛋白-1，髓过氧化物酶，钙网蛋白，半乳糖凝集素-3和PD-L1的表达与帕比司他的疗效在空间上相关，帕比司他是一种泛HDAC抑制剂，先前显示可诱导免疫原性细胞死亡并与抗PD-1在乳腺癌中协同作用。然而，PD-L1本身并不是一个可靠的预测因子。相反，通过原位热点检测富含细胞死亡并被ICAM-1和神经纤毛蛋白-1阳性的抗肿瘤细胞毒性中性粒细胞浸润的半乳糖凝集素-3阳性非增殖肿瘤区，有力地鉴定了ICB疗效。这种热点可以使用基于距离的聚类分析来特异性地检测。肿瘤微环境中功能状态的单细胞测量表明，定性和定量效应都可能驱动有效的治疗反应。总的来说，本研究提供了（i）关于乳腺癌诱导抗肿瘤免疫的最早细胞事件的补充生物学知识，包括耐药癌症干细胞的出现，以及（ii）以特定空间细胞关联形式新鉴定的生物标志物。该方法使用基于标准细胞类型、IHC和FFPE的技术，因此原位生物标志物的空间聚类可以很容易地整合到现有的临床或研究工作流程中，包括管腔乳腺癌。由于检测到早期药物反应，生物标志物可能特别适用于机会之窗临床试验，以快速区分反应和耐药患者，从而限制不必要的治疗相关毒性。
Immunotherapies, including anti-PD-1 immune checkpoint blocking (ICB) antibodies, have revolutionized the treatment of many solid malignancies. However, their efficacy in breast cancer has been limited to a subset of patients with triple-negative breast cancer, where ICBs are routinely combined with a range of cytotoxic and targeted agents. Reliable biomarkers predictive of the therapeutic response to ICB in breast cancer are critically missing, though a combination response has been associated with immunogenic cell death (ICD). Here, we utilized a recently developed integrated analytical platform, the multiplex implantable microdevice assay (MIMA), to evaluate the presence and spatial cell relations of literature-based candidate markers predictive of ICB efficacy in luminal mouse mammary carcinoma. MIMA integrates (i) an implantable microdevice for the localized delivery of small amounts of drugs inside the tumor bed with (ii) sequential multiplex immunohistochemistry (mIHC) and spatial cell analysis pipelines to rapidly (within days) describe drug mechanisms of action and find predictive biomarkers in complex tumor tissue. We show that the expression of cleaved caspase-3, ICAM-1, neuropilin-1, myeloperoxidase, calreticulin, galectin-3, and PD-L1 were spatially associated with the efficacy of panobinostat, a pan-HDAC inhibitor that was previously shown to induce immunogenic cell death and synergize with anti-PD-1 in breast cancer. PD-L1 by itself, however, was not a reliable predictor. Instead, ICB efficacy was robustly identified through the in situ hotspot detection of galectin-3-positive non-proliferating tumor zones enriched in cell death and infiltrated by anti-tumor cytotoxic neutrophils positive for ICAM-1 and neuropilin-1. Such hotspots can be specifically detected using distance-based cluster analyses. Single-cell measurements of the functional states in the tumor microenvironment suggest that both qualitative and quantitative effects might drive effective therapy responses. Overall, the presented study provides (i) complementary biological knowledge about the earliest cell events of induced anti-tumor immunity in breast cancer, including the emergence of resistant cancer stem cells, and (ii) newly identified biomarkers in form of specific spatial cell associations. The approach used standard cell-type-, IHC-, and FFPE-based techniques, and therefore the identified spatial clustering of in situ biomarkers can be readily integrated into existing clinical or research workflows, including in luminal breast cancer. Since early drug responses were detected, the biomarkers could be especially applicable to window-of-opportunity clinical trials to rapidly discriminate between responding and resistant patients, thus limiting unnecessary treatment-associated toxicities.
登录
查看更多内容
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
DOI：
10.1084/jem.20050915
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casares N;Pequignot MO;Tesniere A;Ghiringhelli F;Roux S;Chaput N;Schmitt E;Hamai A;Hervas-Stubbs S;Obeid M;Coutant F;Métivier D;Pichard E;Aucouturier P;Pierron G;Garrido C;Zitvogel L;Kroemer G
通讯作者：
Kroemer G
影响因子：
64.8
作者：
Guerriero JL;Sotayo A;Ponichtera HE;Castrillon JA;Pourzia AL;Schad S;Johnson SF;Carrasco RD;Lazo S;Bronson RT;Davis SP;Lobera M;Nolan MA;Letai A
通讯作者：
Letai A
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.