PD-L1 inhibition promotes type I interferon responses, enhancing chemotherapy-induced cytotoxicity in cancer cells
PD-L1 抑制促进 I 型干扰素反应,增强化疗诱导的癌细胞细胞毒性
基本信息
- 批准号:10318664
- 负责人:
- 金额:$ 5.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-12-14 至 2022-03-04
- 项目状态:已结题
- 来源:
- 关键词:Advanced Malignant NeoplasmAffectAntibodiesAntineoplastic AgentsBinding SitesBlocking AntibodiesCarboplatinCell DeathCell LineCellsCessation of lifeCisplatinClinicalCombined Modality TherapyDataEmpiricismEtoposideFDA approvedImmuneImmune responseImmune systemImmunoglobulin GImmunotherapyIn VitroInterferon Type IInterferonsLifeMalignant Epithelial CellMalignant NeoplasmsMediatingMonitorMusNon-Small-Cell Lung CarcinomaPDL1 inhibitorsPaclitaxelPatientsPharmaceutical PreparationsPhosphorylationReagentReportingResistanceRoleSTAT1 geneSTAT2 geneSignal TransductionStructureT-Cell ActivationT-LymphocyteTestingTherapeuticTherapeutic AgentsTimeToxic effectTyrosine PhosphorylationWorkanti-PD-L1anti-PD-L1 antibodiesanti-cancerbasecancer cellcancer therapycell killingchemotherapeutic agentchemotherapycytotoxicityefficacy evaluationgemcitabinehumanized monoclonal antibodiesimmune checkpoint blockadeimmunological statusimprovedin vitro Modelin vivoin vivo Modelinnovationknock-downlung cancer celllung small cell carcinomaneoplastic cellpre-clinicalprogrammed cell death ligand 1response
项目摘要
PROJECT SUMMARY
Immune checkpoint blockade (ICB), for example using anti-PD-L1, is a landmark advance for treating advanced
cancers but is nevertheless still effective in all too few patients. Thus, extensive efforts are directed at identifying
combination therapeutic strategies to improve response rates. We have discovered that PD-L1, in addition to its
role in blocking T cell activation, protects cancer cells against specific chemotherapeutic agents, e.g., cisplatin.
Importantly, this mechanism operates independently of T cell recognition of tumor and the cell-extrinsic immune
system. We found that PD-L1 inhibits the ability of cancer cells to respond to type I interferon (IFN-I) and that
cancer cell-intrinsic responses to IFN-I are critical in increasing cisplatin cytotoxicity. We hypothesize that PD-
L1 inhibitors will enhance the ability of IFN-I to sensitize cancer cells to chemotherapy by a cancer-cell intrinsic
mechanism, independently of the immune system. Here, we propose to identify chemotherapeutic agents and
IFN-I as logical drugs to combine with ICB, to increase response rates in an immune-independent manner.
Aim 1. Determine the ability of the anti-PD-L1 ICB to enhance IFN-I responses and cisplatin toxicity in
lung cancer cells. FDA-approved anti-PD-L1s (atezolizumab, avelumab, and durvalumab) are currently in
clinical use to activate anti-cancer immune responses. However, it has not been assessed how efficiently each
FDA-approved anti-PD-L1 blocks the cancer cell-intrinsic immune-independent function of PD-L1. We will
determine which antibody against PD-L1 enhances IFNβ responses and cisplatin cytotoxicity in small cell lung
carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) cell lines, using Western analysis and IncuCyte
real-time cell monitoring. Aim 2. Define the spectrum of therapeutic agents whose cytotoxicity is enhanced
by inhibiting PD-L1. Each chemotherapeutic agent will be affected differently by the cancer cell-intrinsic
function of PD-L1, since each induces cell death by different mechanisms. We will determine which
chemotherapeutic agent kills cancer cells more efficiently in combination with PD-L1 inhibition (knock-down of
PD-L1 or treating with selected antibodies against PD-L1) alone, or by using PD-L1 inhibition plus IFN-I in SCLC
cells. Aim 3. Generate pre-clinical in vivo proof of principle for rational combination therapy. After
selecting the most efficient combination in vitro in SCLC and NSCLC cell lines, we will evaluate the efficacy of
the combination treatment in vivo in NSG mice, which lack most of the immune system, to cleanly evaluate the
cancer cell-intrinsic immune-independent PD-L1-mediated effects.
Impact. The studies proposed here are highly innovative as they propose a paradigm-shifting approach in which
PD-L1 inhibitors are used as reagents to enhance the ability of IFN-I to sensitize cancer cells to chemotherapy
in an immune-independent mechanism. This work will lead to improved understanding of a relatively unexplored
facet of anti-PD-L1 activity, in ways that will lead to rational combination treatments for patients, regardless of
their pre-existing immune status, to hopefully meaningfully increase response rates.
项目摘要
免疫检查点阻断(ICB),例如使用抗PD-L1,是治疗晚期
癌症,但仍然在所有太少的患者中有效。因此,广泛的努力是针对确定
联合治疗策略,以提高反应率。我们已经发现PD-L1除了其
在阻断T细胞活化中的作用,保护癌细胞对抗特异性化疗剂,例如,顺铂
重要的是,这种机制的运作独立于T细胞识别肿瘤和细胞外源性免疫。
系统我们发现PD-L1抑制癌细胞对I型干扰素(IFN-I)的反应能力,
癌细胞对IFN-1的内在应答在增加顺铂的细胞毒性中是关键的。我们假设PD-
L1抑制剂将增强IFN-1通过癌细胞内在的免疫调节作用使癌细胞对化疗敏感的能力。
机制,独立于免疫系统。在这里,我们建议识别化疗药物,
IFN-I作为逻辑药物与ICB联合收割机结合,以免疫非依赖的方式增加应答率。
目标1。确定抗PD-L1 ICB增强IFN-1应答和顺铂毒性的能力,
肺癌细胞。FDA批准的抗PD-L1(atezolizumab、avelumab和durvalumab)目前在
用于激活抗癌免疫应答的临床用途。然而,还没有评估每一种方法的效率如何。
FDA批准的抗PD-L1阻断PD-L1的癌细胞内在免疫独立功能。我们将
确定哪种抗PD-L1抗体增强小细胞肺中IFNβ应答和顺铂细胞毒性
癌(SCLC)和非小细胞肺癌(NSCLC)细胞系,使用Western分析和IncuCyte
实时细胞监测。目标二。定义细胞毒性增强的治疗药物谱
通过抑制PD-L1。每种化学治疗剂将受到癌细胞内在的免疫调节的不同影响。
PD-L1的功能,因为每种都通过不同的机制诱导细胞死亡。我们将决定
化疗剂与PD-L1抑制(敲低PD-L1)的组合更有效地杀死癌细胞。
PD-L1或用选定的抗PD-L1抗体治疗),或通过在SCLC中使用PD-L1抑制剂加IFN-I
细胞目标3.为合理的联合治疗生成临床前体内原理证明。后
在SCLC和NSCLC细胞系中选择最有效的体外组合,我们将评估
在缺乏大部分免疫系统的NSG小鼠中进行体内联合治疗,以清楚地评估
癌细胞内在免疫非依赖性PD-L1介导的效应。
冲击这里提出的研究是高度创新的,因为他们提出了一种范式转变的方法,
PD-L1抑制剂被用作增强IFN-I使癌细胞对化疗敏感的能力的试剂
在一个免疫独立的机制。这项工作将导致更好地了解一个相对未开发的
抗PD-L1活性的一个方面,以某种方式为患者提供合理的联合治疗,
他们预先存在的免疫状态,希望有意义地提高反应率。
项目成果
期刊论文数量(0)
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HyeonJoo Cheon其他文献
HyeonJoo Cheon的其他文献
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{{ truncateString('HyeonJoo Cheon', 18)}}的其他基金
PD-L1 inhibition promotes type I interferon responses, enhancing chemotherapy-induced cytotoxicity in cancer cells
PD-L1 抑制促进 I 型干扰素反应,增强化疗诱导的癌细胞细胞毒性
- 批准号:
10621060 - 财政年份:2022
- 资助金额:
$ 5.4万 - 项目类别:
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