Modeling Primary Tumor Organoids for lmmunotherapy

用于免疫治疗的原发性肿瘤类器官建模

• 批准号: 10350712
• 负责人: Ning Cheng
• 金额: $ 10.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350712
• 关键词: Adjuvant; Adjuvant Therapy; Agonist; Antitumor Response; Area; Biological; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Patient; Cause of Death; Cells; Cessation of life; Clinical Trials; Combined Modality Therapy; Complement; Cytosol; Development; Dinucleoside Phosphates; Disadvantaged; Drug Delivery Systems; Drug or chemical Tissue Distribution; Ensure; Excision; Gene Expression; Genetic Engineering; Genetically Engineered Mouse; Goals; Harvest; Head and Neck Cancer; Immune; Immune response; Immunotherapy; In Vitro; Infection; Inflammatory Response; Innate Immune Response; Liposomes; Long-Term Effects; Malignant Neoplasms; Metastatic Neoplasm to the Lung; Modeling; Monitor; Nanotechnology; Natural Killer Cells; Operative Surgical Procedures; Organoids; Particulate; Patients; Periodicity; Phase; Population; Prevention; Prevention therapy; Primary Neoplasm; Production; Property; Radiation therapy; Recurrence; Relapse; Research; Research Personnel; Resistance; Role; Site; Stimulator of Interferon Genes; System; Testing; Therapeutic; Tissues; Training; Treatment Protocols; Tumor-associated macrophages; Vaccine Adjuvant; Work; adaptive immunity; anti-PD-L1 antibodies; anti-cancer; anti-tumor immune response; anticancer research; cancer genetics; cancer immunotherapy; cancer prevention; cancer therapy; cancer type; chemotherapy; clinical predictors; controlled release; cytokine; engineered T cells; gut microbiota; histocompatibility gene; immune checkpoint blockade; immunogenicity; improved; interest; macrophage; malignant breast neoplasm; melanoma; microbiome; microbiota; nanoparticle; neoplastic cell; new technology; oral microbial community; particle; prevent; programmed cell death ligand 1; programmed cell death protein 1; receptor; refractory cancer; response; restoration; subcutaneous; tumor; tumor microenvironment; tumorigenic; uptake

Abstract Cancer ranks as the second leading cause of death, contributing to nearly 1 in every 4 death in the US. Current cancer immunotherapies, especially checkpoint blockade, is largely influenced by PD-L1 expression in tumors; and patients with limited PD-L1 positive expression are normally less responsive to the immunotherapy. These findings suggest new technologies are needed to for PD-L1 resistant tumors. Cyclic [G(3',5')pA(3',5')p] (cGAMP) has recently emerged as an exciting new class of vaccine adjuvants, which sequentially activate innate immune responses and orchestrate adaptive immunity. Tumor associated macrophages (TAMs), a major type of immune cells in tumor microenvironment, are a potent target for adjuvant therapy. Particulate systems are ideal vehicles for targeting TAM population within tumor. Additionally, combination therapy holds great promise for tumor prevention and treatment. Most important, the critical role of cancer microbiome is gaining increased interests for cancer therapy. We hypothesize that Particulate cGAMP adjuvants targeting TAMs can enhance anti-tumor immune response and reverse the pro-tumorigenic microenvironment in both PD-L1 responsive and resistant cancers, and improve the anti-tumor efficiency in combination with checkpoint blockade and tumor resection. We have tested and will continue to test the hypothesis using B16F10 melanoma (subcutaneous and lung metastasis models; PD-L1 responsive) and C3(1)Tag basal-like breast cancer (orthotopic and spontaneous GEM models; PD-L1 resistant), and test the following specific aims: Aim 1. Particulate delivery of STING agonist as anti-cancer immuotherapeutics: (F99 phase). We optimized liposomal NP and Ace-DEX MP delivery systems for cGAMP to evaluate the cellular uptake and M2->M1 skewing capacity, and detect major histocompatibility (MHC) gene and costimulatory gene expression and cytokine production in vitro. We also investigated the tissue distribution of particulate cGAMPs and their anti-tumor efficacy in above-mentioned tumor models. Aim 2. Mechanism by which particulate delivery of STING agonist acts an as anti-cancer immuotherapeutic and combination therapies: (F99 phase). We will study the role of macrophage, CD4+ and CD8+ T cells, and NK cells in anti-tumor response of particulate cGAMPs. We will also monitor long term survival and tumor recurrence by combination therapies of particulate cGAMPs with anti-PD-L1 antibodies and tumor resection in above- mentioned tumor models. Aim 3. The Postdoctoral Research Direction (K00 phase). I will pursue my interest in understanding the mechanism and functional role of gut microbiota in host response to cancer development and therapy, meanwhile, with a particular interest in studying the role of oral microbiota in response to head and neck cancer therapeutics and restoration.

摘要 癌症是第二大死亡原因，在美国，每4例死亡中就有1例是癌症造成的。电流 癌症免疫疗法，特别是检查点阻断，在很大程度上受肿瘤中PD-L1表达的影响; 并且具有有限PD-L1阳性表达的患者通常对免疫疗法的反应较低。这些 研究结果表明，需要新技术来治疗PD-L1耐药肿瘤。环[G（3'，5'）pA（3'，5'）p]（cGAMP） 最近作为一种令人兴奋的新型疫苗佐剂出现， 反应和协调适应性免疫。肿瘤相关巨噬细胞（TAM），一种主要类型的免疫细胞， 肿瘤微环境中的细胞是辅助治疗的有效靶点。微粒系统是理想的交通工具 用于靶向肿瘤内的TAM群体。此外，联合治疗对肿瘤有很大的希望。 预防和治疗。最重要的是，癌症微生物组的关键作用越来越受到关注 用于癌症治疗。我们假设靶向TAM的颗粒状cGAMP佐剂可以增强抗肿瘤作用。 免疫应答和逆转PD-L1应答和耐药患者的促肿瘤微环境 癌症，并结合检查点阻断和肿瘤切除提高抗肿瘤效率。 我们已经并将继续使用B16 F10黑色素瘤（皮下和肺）测试该假设 转移模型; PD-L1应答）和C3（1）Tag基底样乳腺癌（原位和自发性GEM 模型; PD-L1耐药），并测试以下具体目标：目标1. STING激动剂的颗粒递送作为 抗癌免疫治疗：（F99期）。我们优化了脂质体NP和Ace-DEX MP递送系统， 用于cGAMP，以评估细胞摄取和M2->M1偏斜能力，并检测主要组织相容性 (MHC)基因和共刺激基因的表达和细胞因子的产生。我们还调查了 颗粒状cGAMP的分布及其在上述肿瘤模型中的抗肿瘤功效。目标二。 STING激动剂的颗粒递送作为抗癌免疫剂起作用的机制和 联合治疗：（F99期）。我们将研究巨噬细胞，CD 4+和CD 8 + T细胞，以及NK细胞的作用。 细胞在颗粒状cGAMP的抗肿瘤应答中的作用。我们还将监测长期生存和肿瘤复发情况 通过颗粒状cGAMP与抗PD-L1抗体和肿瘤切除的联合治疗， 提到了肿瘤模型。目标3。博士后研究方向（K 00阶段）。我会继续我的兴趣 了解肠道微生物群在宿主对癌症发展的反应中的机制和功能作用， 治疗，同时，特别感兴趣的是研究口腔微生物群在头部和颈部反应中的作用， 癌症治疗和恢复。

项目成果

Targeting Innate Immunity in Breast Cancer Therapy: A Narrative Review.

• DOI: 10.3389/fimmu.2021.771201
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Ye Y;Xu C;Chen F;Liu Q;Cheng N
• 通讯作者: Cheng N

Immune receptor inhibition through enforced phosphatase recruitment.

• DOI: 10.1038/s41586-020-2851-2
• 发表时间: 2020-10
• 期刊: Nature
• 影响因子: 64.8
• 作者: Fernandes RA;Su L;Nishiga Y;Ren J;Bhuiyan AM;Cheng N;Kuo CJ;Picton LK;Ohtsuki S;Majzner RG;Rietberg SP;Mackall CL;Yin Q;Ali LR;Yang X;Savvides CS;Sage J;Dougan M;Garcia KC
• 通讯作者: Garcia KC