Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1

通过阻断肿瘤和脂肪 DDR1 来增强抗肿瘤免疫力

• 批准号: 9980667
• 负责人: Rong Li
• 金额: $ 47.69万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9980667
• 关键词: Address; Adipocytes; Adipose tissue; Adoptive Transfer; Antitumor Response; Attenuated; Binding; Biological Assay; Breast Cancer Model; Breast Cancer Patient; Cancer Biology; Cell Compartmentation; Cell physiology; Cells; Clinical; Clinical Oncology; Coculture Techniques; Collagen; Collagen Fibril; Collagen Receptors; Communication; Complex; Data; Development; Diet; Extracellular Domain; Future; Human; Immune; Immunocompetent; Immunologics; Immunooncology; Immunophenotyping; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; In complete remission; Infiltration; Integration Host Factors; Knock-out; Knockout Mice; Knowledge; Ligands; Literature; Mammary Neoplasms; Mediating; Molecular; Mus; New Agents; Non obese; Obesity; Obesity associated cancer; Patient-Focused Outcomes; Patients; Phosphotransferases; Positioning Attribute; Production; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Reporting; Resistance; Role; Sampling; Signal Transduction; Stromal Neoplasm; Technology; Testing; Time; Tissues; Tumor Immunity; Woman; anti-tumor immune response; attenuation; base; cancer immunotherapy; cell type; comorbidity; cytokine; discoidin domain receptor 1; experimental study; immunoregulation; malignant breast neoplasm; migration; mouse genetics; mouse model; multidisciplinary; neoplastic cell; novel; patient subsets; response; targeted treatment; tool; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor progression

ABSTRACT Despite significant clinical breakthroughs in anticancer immunotherapy, the efficacy of current immunotherapies in breast cancer is modest. Only a small fraction of breast cancer patients have a clinical response; complete responses to these agents are exceedingly rare. The underlying mechanisms of tissue- specific immune regulation in breast cancer remains to be elucidated. Furthermore, how comorbidities such as obesity influence antitumor immunity in breast cancer is even less understood. Discoidin domain receptor 1 (DDR1) is a collagen receptor with an intrinsic tyrosine kinase activity. High DDR1 expression in breast cancer is associated with poor patient outcomes and attenuated antitumor immunity. We found complex tumor-promoting actions for both tumor and adipose DDR1 in the breast tumor microenvironment. Tumor DDR1 suppresses antitumor immunity, whereas adipose DDR1 is required for diet- induced obesity, tumor-promoting cytokine production, and immune modulation. Our preliminary data further indicate that the shed extracellular domain of DDR1 alone is sufficient for its functions in tumor and adipose cells, which has not previously been reported. We therefore hypothesize that DDR1 in the breast tumor microenvironment promotes tumor progression by dampening antitumor immunity, enabling adiposity, and abetting immune-adipose cell-tumor crosstalk. We predict that blocking kinase-independent DDR1 signals can boost antitumor immunity and response to anticancer immunotherapies, especially in patients with obesity. To test this hypothesis, in this R01 application, we will determine how tumor DDR1 suppresses antitumor immunity (Aim 1), how adipose DDR1 contributes to obesity-associated cancer progression (Aim 2), and how DDR1 carries out its immune-suppressive functions independent of its kinase activity (Aim 3). With combined expertise in cancer biology, tumor immunology, and clinical oncology, our multidisciplinary team is well positioned to validate our novel hypothesis. The fact that DDR1 has distinct functions in different cell compartments of the breast tumor microenvironment underscores the complexity of tumor-stromal interactions. By investigating tumor and adipose DDR1 in an integrative and comprehensive manner as proposed here, we will fill major gaps of knowledge about tumor-initiated immune suppression and obesity-associated comorbid effects. Given the adipocyte-rich tumor microenvironment in breast cancer and the growing numbers of patients with obesity and breast cancer, our proposed studies address an unmet clinical need and promise to inform the development of new strategies to enhance antitumor immunity for breast cancer patients, especially for those with obesity. !

抽象的 尽管抗癌免疫疗法在临床上取得了重大突破，但目前的疗效 乳腺癌的免疫疗法效果不大。只有一小部分乳腺癌患者有临床症状 回复;对这些药物的完全反应极为罕见。组织的基本机制- 乳腺癌中的特异性免疫调节仍有待阐明。此外，如何合并症，例如 肥胖对乳腺癌抗肿瘤免疫的影响更是鲜为人知。 Discoidin 结构域受体 1 (DDR1) 是一种具有内在酪氨酸激酶活性的胶原蛋白受体。高的 乳腺癌中的 DDR1 表达与患者预后不良和抗肿瘤作用减弱有关 免疫。我们发现乳腺肿瘤中肿瘤和脂肪 DDR1 具有复杂的促肿瘤作用 微环境。肿瘤 DDR1 抑制抗肿瘤免疫，而脂肪 DDR1 是饮食所必需的。 诱导肥胖、促进肿瘤细胞因子的产生和免疫调节。我们的初步数据进一步 表明 DDR1 脱落的细胞外结构域足以发挥其在肿瘤和脂肪中的功能 细胞，此前未曾报道过。因此，我们假设乳腺肿瘤中的 DDR1 微环境通过抑制抗肿瘤免疫、促进肥胖和促进肿瘤进展 促进免疫-脂肪细胞-肿瘤串扰。我们预测阻断激酶独立的 DDR1 信号可以 增强抗肿瘤免疫力和抗癌免疫疗法的反应，尤其是肥胖患者。到 检验这个假设，在这个 R01 应用中，我们将确定肿瘤 DDR1 如何抑制抗肿瘤 免疫（目标 1）、脂肪 DDR1 如何促进肥胖相关癌症进展（目标 2）以及如何 DDR1 执行其免疫抑制功能，与其激酶活性无关（目标 3）。与组合 我们的多学科团队在癌症生物学、肿瘤免疫学和临床肿瘤学方面拥有丰富的专业知识 旨在验证我们的新假设。 DDR1 在乳腺肿瘤的不同细胞区室中具有不同的功能 微环境强调了肿瘤-基质相互作用的复杂性。通过研究肿瘤和 在此提出的以综合全面的方式开发脂肪DDR1，我们将填补以下领域的主要空白： 关于肿瘤引发的免疫抑制和肥胖相关共病效应的知识。鉴于 乳腺癌中富含脂肪细胞的肿瘤微环境以及越来越多的肥胖患者和 乳腺癌，我们提出的研究解决了未满足的临床需求，并承诺为乳腺癌的发展提供信息 增强乳腺癌患者（尤其是肥胖患者）抗肿瘤免疫力的新策略。 ！