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. !

项目摘要：共生微生物群在免疫调节中起着重要作用。由于 我们对癌症疗法有效性的机制的理解的最新进展，肠道 在调节各种免疫疗法的效率方面已隐含菌群。肿瘤细胞表达 CD47是跨膜蛋白信号传导“不要吃我”到吞噬细胞，可促进免疫进化和 值得注意的是，已经观察到差异抗CD47抗体诱导的肿瘤对照，我们的 初步数据表明，不同的共生微生物群对CD47产生不同的抗肿瘤反应 封锁：1）杰克逊实验室（JAX）的含肿瘤的野生型（WT）小鼠对CD47封锁的反应更好 与塔科克农场（TAC）的肿瘤小鼠相比，免疫疗法（TAC）； 2）消除抗生素喂养 JAX的WT小鼠中的抗肿瘤反应； 3）与JAX小鼠共同体后，增强了肿瘤控制 在CD47桶之后的TAC小鼠中； 4）在无菌（GF）WT小鼠中未检测到抗肿瘤作用 CD47封锁之后； 5）通过口服转移抗CD47诱导的肿瘤对照的差异 粪便菌群的饲料。 假设：我们假设肠道微生物群调节CD47引起的抗肿瘤免疫反应 可以解释先前观察到的差异治疗反应的块。 目标1：研究与肠道菌群如何控制抗抗菌有关的细胞和分子机制 抗CD47抗体治疗引起的肿瘤作用。 目标2：鉴定CD47封锁后介导抗肿瘤免疫组织化学的菌群物种。 变革势：检查点抑制剂已转化了人类癌症的治疗 恶性黑色素瘤和肺癌；但是，这些新生的免疫调节方法已被证明 到目前为止，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，该肠道微生物组适合免疫疗法的抗肿瘤作用和 化学疗法，共生微生物群的状态和影响目前尚未被广泛视为一部分 在标准实践中，即使许多癌症患者目前或 在治疗过程中，诸如治疗毒性和感染等适应症。这项研究有 改变临床实践的潜力：确定潜在的微生物群的存在或不存在 CD47封锁可以改善抗肿瘤作用，并扩大对此做出反应的患者人群 免疫检查点抑制剂目前正在临床试验中。