Microbiota and the anti-tumor action of anti-CD47 immunomodulation.

微生物群和抗 CD47 免疫调节的抗肿瘤作用。

• 批准号: 9814981
• 负责人: RALPH R WEICHSELBAUM
• 金额: $ 17.62万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-06 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9814981
• 关键词: 16S ribosomal RNA sequencing; Analysis of Variance; Anti-CD47; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Therapy; Antitumor Response; Autoimmune Diseases; Bacteria; Bacteroides fragilis; Bifidobacterium; CD47 gene; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Patient; Clinical Data; Clinical Trials; Computer software; Cross-Priming; Cyclic GMP; Cytosol; Data; Development; Eating; Effectiveness; Farming environment; Flow Cytometry; Germ-Free; Human; Immune; Immune Evasion; Immune checkpoint inhibitor; Immunity; Immunotherapy; Infection; Integral Membrane Protein; Interferon Type I; Interferon Type II; Interferons; Investigation; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mitochondrial DNA; Molecular; Mus; NADPH Oxidase; Oral; Phagocytes; Phagocytosis; Play; Predisposition; Probiotics; Production; Public Health; Regulation; Relapse; Reporting; Role; SHPS-1 protein; Signal Transduction; Signaling Protein; Solid; Statistical Data Interpretation; T cell response; Testing; Toxic effect; Trees; Tumor Burden; Tumor Immunity; Variant; Wild Type Mouse; Work; anti-PD-L1; anti-tumor immune response; antitumor effect; beta diversity; cancer therapy; chemotherapy; clinical practice; commensal microbes; enzyme linked immunospot assay; fecal microbiota; feeding; gut bacteria; gut microbiome; gut microbiota; immune checkpoint; immunoregulation; improved; interest; macrophage; melanoma; microbiota; neoplastic cell; patient population; patient subsets; pre-clinical; recruit; response; therapeutic target; translational impact; treatment response; tumor

Project Summary: The commensal microbiota plays a prominent role in the regulation of immunity. Due to recent advances in our understanding of mechanisms underlying the efficacy of cancer therapies, the gut microbiota has been implicated in modulating the efficacy of various immunotherapies. Tumor cell expression of CD47, a transmembrane protein signaling “don’t eat me” to phagocytes, promotes immune evasion and tumor relapse. Notably, differential anti-CD47 antibody-induced tumor control has been observed, and our preliminary data indicate that different commensal microbiota produce different anti-tumor responses to CD47 blockade: 1) Tumor-bearing wild-type (WT) mice from Jackson Labs (Jax) responded better to CD47 blockade immunotherapy compared with tumor-bearing mice from Taconic Farms (Tac); 2) antibiotic feeding eliminated the anti-tumor responses in WT mice from Jax; 3) after cohousing with Jax mice, tumor control was enhanced in Tac mice following CD47 blockade; 4) anti-tumor effects were not detected in Germ-Free (GF) WT mice after CD47 blockade; and 5) differences in anti-CD47-induced tumor control were transferred through oral gavage of fecal microbiota. HYPOTHESIS: We hypothesize that the gut microbiota modulate anti-tumor immune responses elicited by CD47 blockade, which could explain the previously observed differential therapeutic responses. Aim 1: Investigate the cellular and molecular mechanisms related to how gut microbiota govern anti- tumor effects induced by anti-CD47 antibody treatment. Aim 2: Identification of microbiota species that mediate antitumor immunity after CD47 blockade. TRANSFORMATIVE POTENTIAL: Checkpoint inhibitors have transformed the treatment of human cancers such as malignant melanoma and lung cancer; however, these nascent immunomodulatory approaches have proven effective thus far in only a subset of patients. While limited preclinical and clinical data suggest that probiotic treatment can promote a gut microbiome that is amenable to the antitumor effects of immunotherapies and chemotherapies, the status and effects of commensal microbiota are currently not widely considered as part of standard practice, even though many cancer patients currently receive pro- and/or antibiotics prior to or during the course of their treatment, for indications such as treatment toxicity and infection. This study has the potential to change clinical practice: determination of the presence or absence of microbiota that potentiates CD47 blockade could improve anti-tumor effects, and expand the patient population that responds to this immune checkpoint inhibitor currently in clinical trials. !

项目概述：肠道微生物群在免疫调节中起着重要作用。由于 我们对癌症治疗有效性机制的理解的最新进展， 微生物群参与调节各种免疫疗法的功效。肿瘤细胞表达 CD 47是一种跨膜蛋白，向吞噬细胞发出“不要吃我”的信号，促进免疫逃避， 肿瘤复发值得注意的是，已经观察到差异性抗CD 47抗体诱导的肿瘤控制，并且我们的研究发现， 初步数据表明，不同的肠道微生物群对CD 47产生不同的抗肿瘤反应， 阻断：1）来自杰克逊实验室（Jax）的携带肿瘤的野生型（WT）小鼠对CD 47阻断反应更好 免疫治疗与Taconic Farms（Tac）的荷瘤小鼠相比; 2）消除抗生素喂养 野生型小鼠的抗肿瘤反应; 3）与Jax小鼠共住后，肿瘤控制增强 4）在无菌（GF）WT小鼠中未检测到抗肿瘤作用 CD 47阻断后;和5）抗CD 47诱导的肿瘤控制的差异通过口服转移 灌胃粪便微生物群。 假设：我们假设肠道微生物群调节由CD 47诱导的抗肿瘤免疫应答。 阻断，这可以解释以前观察到的差异治疗反应。 目的1：研究与肠道微生物群如何调控抗肿瘤相关的细胞和分子机制。 抗CD 47抗体治疗诱导的肿瘤效应。 目的2：鉴定在CD 47阻断后介导抗肿瘤免疫的微生物群物种。 转化潜力：检查点抑制剂已经改变了人类癌症的治疗， 恶性黑色素瘤和肺癌;然而，这些新生的免疫调节方法已经证明， 迄今为止仅在一部分患者中有效。虽然有限的临床前和临床数据表明，益生菌 治疗可以促进肠道微生物组，其适合免疫疗法的抗肿瘤作用， 由于化疗，肠道微生物群的状态和影响目前没有被广泛认为是化疗的一部分， 尽管许多癌症患者目前在化疗之前或之后接受了抗生素和/或抗生素， 在其治疗过程中，针对诸如治疗毒性和感染的适应症。这项研究有 改变临床实践的可能性：确定是否存在增强 CD 47阻断可以改善抗肿瘤作用，并扩大对此有反应的患者群体。 免疫检查点抑制剂目前在临床试验中。!