Regulating Intratumoral Leukocytes to Improve Response to Chemotherapy

调节瘤内白细胞以改善化疗反应

• 批准号: 9031228
• 负责人: Brian Ruffell
• 金额: $ 24.9万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031228
• 关键词: Address; Adjuvant; Adjuvant Chemotherapy; Agonist; Breast Cancer Treatment; Breast Carcinoma; CD8B1 gene; Carcinoma; Cell Death; Cell physiology; Cessation of life; Clinical; Clinical Trials; Combination Drug Therapy; Dendritic Cells; Dendritic cell activation; Disease; Disease-Free Survival; Genomics; Hormone Receptor; Hormones; Immune; Immune response; In complete remission; Incidence; Individual; Infiltration; Interleukin-10; Interleukin-12; Leukocytes; Lymphocyte; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Molecular; Mus; Neoadjuvant Therapy; Pathologic; Patient Monitoring; Patients; Phenocopy; Production; Recruitment Activity; Recurrence; Refractory; Regimen; Role; Solid; Source; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Transgenic Mice; Woman; base; chemotherapy; cytokine; cytotoxic; experience; improved; insight; interleukin-10 receptor; macrophage; malignant breast neoplasm; mouse model; novel therapeutics; outcome forecast; prevent; receptor; response; standard of care; tumor; unpublished works

PROJECT SUMMARY The majority of patients with solid malignancies undergo chemotherapeutic regimens either in the adjuvant or neoadjuvant setting. Response to chemotherapy is not solely dependent upon the genomic aberrations present within tumors, as it is also contingent upon the infiltration and effector function of cytotoxic lymphocytes, based upon the strong clinical association of CD8+ T cell infiltration with response rates in multiple carcinomas, and supporting evidence of a functional role from implantable mouse tumor models. Enhancing the CD8+ T cell response during chemotherapy therefore has the potential to improve pathologic complete response rates and extend patient survival. We have recently demonstrated using a transgenic mouse model of mammary carcinoma that tumor-associated macrophages abrogate the CD8+ T cell-dependent response during chemotherapy. In unpublished work, we have now identified that this suppressive activity is derived from production of interleukin 10 (IL10), as macrophages are the primary source of interleukin 10 within tumors, and IL10 receptor (IL10R) blockade phenocopies the effects of macrophage antagonists during a chemotherapeutic response. While interleukin 10 does not directly suppress CD8+ T cell proliferation or function, we observe increased infiltration of intratumoral dendritic cells and expression of interleukin 12 following treatment with macrophage antagonists in combination chemotherapy. We therefore hypothesize that interleukin 10 suppresses activation of dendritic cells following chemotherapy-induced cell death, thereby preventing reactivation of intratumoral CD8+ T cells and offering a tractable target for improving immune responses during chemotherapy. To test these hypotheses we propose the following specific aims: Determine the functional significance of intratumoral dendritic cell activation in regulating response to chemotherapy following IL10R blockade; determine the functional contribution of intratumoral versus recruited CD8+ T cells in mediating response to chemotherapy following IL10R blockade; and compare durability of anti-tumor immune responses following IL10R blockade and chemotherapy in combination with immune-checkpoint blockade versus co- stimulatory agonists.

项目总结 大多数实体恶性肿瘤患者接受化疗方案，或在辅助或 新佐剂环境。对化疗的反应不仅仅取决于存在的基因组异常 在肿瘤内，因为它也取决于细胞毒性淋巴细胞的渗透和效应功能，基于 在多种癌症中CD8+T细胞的浸润与应答率有很强的临床相关性，以及 从可植入的小鼠肿瘤模型中支持功能作用的证据。增强CD8+T细胞 因此，化疗期间的反应有可能提高病理完全缓解率和 延长患者存活期。我们最近使用转基因小鼠乳腺模型进行了演示。 肿瘤相关巨噬细胞消除CD8+T细胞依赖的反应 化疗。在未发表的工作中，我们现在已经确定这种抑制活动源于 产生白介素10，因为巨噬细胞是肿瘤内白介素10的主要来源，以及 白细胞介素10受体(IL10R)阻断巨噬细胞拮抗剂在化疗中的作用 回应。虽然白介素10并不直接抑制CD8+T细胞的增殖或功能，但我们观察到 丹参治疗后瘤内树突状细胞浸润及白细胞介素12表达增加 联合化疗中的巨噬细胞拮抗剂。因此我们假设白介素10 抑制化疗诱导的细胞死亡后树突状细胞的激活，从而防止 肿瘤内CD8+T细胞的重新激活和为改善免疫反应提供一个易处理的靶点 化疗。为了检验这些假设，我们提出了以下具体目标：确定泛函 肿瘤内树突状细胞活化在调节IL10R化疗疗效中的意义 阻断；确定肿瘤内CD8+T细胞与招募的CD8+T细胞在介导 IL10R阻断后对化疗的反应；并比较抗肿瘤免疫反应的持久性 IL10R阻断和化疗联合免疫检查点阻断与联合应用 刺激性兴奋剂。