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Regulation of inhibitory DAMP to harness immunogenic cell death

调节抑制性 DAMP 以利用免疫原性细胞死亡

基本信息

批准号：
9911207
负责人：
Kazukuni Hayashi
金额：
$ 4.55万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
2020-02-24 至 2023-02-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911207
关键词：
Ablation Activities of Daily Living Address Anabolism Anti-Inflammatory Agents Biology CASP1 gene CD8-Positive T-Lymphocytes Cancer Model Carcinoma Cell Death Cell model Cells Cleaved cell Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Dinoprostone Enzymes Equilibrium Extravasation FDA approved Genetic Genetic Transcription Goals Immune Immune checkpoint inhibitor Immune response Immunity Immunotherapy Infiltration Inflammatory Interleukin-1 beta Intervention Knock-out Knowledge Length Lytic Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Membrane Molecular Nature PTGS2 gene Pattern Peptide Hydrolases Pharmaceutical Preparations Pharmacology Physiological Pilot Projects Poly(ADP-ribose) Polymerases Regulation Reporting Research Role Route Signal Transduction Solid Neoplasm Students T cell response T-Lymphocyte Techniques Testing Therapeutic Translating Treatment Efficacy Tumor Burden anti-cancer base cancer cell cancer therapy cancer type checkpoint therapy chemotherapy clinical application clinically relevant combinatorial cyclooxygenase 2 effectiveness evaluation fascinate gemcitabine immune checkpoint blockade immunogenic cell death immunogenicity improved insight neoplastic cell pre-clinical response success synergism therapeutic target therapy outcome

项目摘要

PROJECT SUMMARY Most anti-cancer therapies designate cell death as the ultimate end goal. Yet, the fascinating biology beyond cell death is emerging as an important contributor to therapeutic outcome. A clinically-relevant example is immunogenic cell death (ICD)—characterized by its functional capacity to potentiate antitumoral T cell immunity. The current defining molecular hallmark of ICD is the release of damage-associated molecular patterns (DAMPs), which function as “danger” signals to ultimately activate T cell immunity. However, our preliminary findings revealed that successful DAMP release alone was insufficient to promote ICD; leading us to challenge this dogma and reason that additional regulatory component(s), other than DAMPs, influence the immunogenicity of cell death. Herein, our new findings also revealed that an inhibitory DAMP (iDAMP) with unclear upstream regulatory mechanisms was concurrently released by dying cells as a physiologic response to chemotherapeutic treatment. Intriguingly, the pharmacological intervention to preclude iDAMP release by dying cells relieved the immunosuppressive constraints imposed by the iDAMP, and readily enabled a non-immunogenic chemotherapy to elicit an antitumoral T cell response. We now propose to elucidate 1) the unexplored upstream regulatory mechanism(s) of the iDAMP and 2) iDAMP blockade as a generalizable strategy to augment antitumoral T cell immunity. Our underlying hypothesis is that pharmacological intervention of the iDAMP axis poses as a paradigm-shifting approach to augment antitumoral T cell immunity and therapeutic efficacy. Knowledge gained from the proposed research will elucidate the upstream mechanism in epithelial cancer cells that regulates iDAMP biosynthesis and release as a physiologic response to anti-cancer therapy, as well as evaluate a therapeutic approach that can alleviate the immunosuppressive constraints of the iDAMP to augment antitumoral T cell immunity. The success of the proposed research will yield a compelling scientific rationale to move the field forward by translating our preclinical findings into clinical application.

项目摘要大多数抗癌疗法将细胞死亡指定为最终目标。然而，细胞之外的迷人生物学死亡正在成为治疗结果的一个重要因素。一个临床相关的例子是免疫原性细胞死亡（ICD）-其特征在于其增强抗肿瘤T细胞免疫的功能能力。目前定义ICD的分子标志是释放损伤相关分子模式（DAMP），其作为“危险”信号起作用以最终激活T细胞免疫。然而，我们的初步发现结果显示，单靠成功的DAMP释放不足以促进ICD的发展，这使我们对这一点提出了挑战。除了DAMP之外的其他调节组分影响免疫原性的教条和理由细胞死亡在此，我们的新发现还揭示了一种上游不清楚的抑制性DAMP（iDAMP），作为对化疗的生理反应，死亡细胞同时释放调节机制治疗有趣的是，阻止死亡细胞释放iDAMP的药物干预减轻了细胞凋亡。 iDAMP施加的免疫抑制限制，并且容易实现非免疫原性化疗引发抗肿瘤T细胞反应。我们现在建议阐明1）未探索的上游调控 iDAMP的机制和2）iDAMP阻断作为增加抗肿瘤T细胞的可推广策略免疫力我们的基本假设是，iDAMP轴的药物干预构成了一个新的机制。范式转变的方法，以增加抗肿瘤T细胞免疫和治疗效果。获得的知识从拟议的研究将阐明上皮癌细胞的上游机制， iDAMP生物合成和释放作为对抗癌治疗生理反应，以及评估可以减轻iDAMP的免疫抑制限制以增强抗肿瘤作用的治疗方法 T细胞免疫拟议研究的成功将产生一个令人信服的科学理由，通过将我们的临床前研究成果转化为临床应用，