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Regulating Intratumoral Leukocytes to Improve Response to Chemotherapy

调节瘤内白细胞以改善化疗反应

基本信息

批准号：
8790105
负责人：
Brian Ruffell
金额：
$ 13.14万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-06 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8790105
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 Health 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breast neoplasm mouse model novel therapeutics outcome forecast prevent receptor response standard of care tumor unpublished works

项目摘要

DESCRIPTION (provided by applicant): 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 In unpublished work, we have now identified that this suppressive activity is derived from production of interleukin 10 (IL10), as macrophages are the primary source of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.

描述（由申请方提供）：大多数实体恶性肿瘤患者在辅助或新辅助治疗环境中接受化疗方案。对化疗的反应不仅仅取决于肿瘤内存在的基因组畸变，因为它还取决于细胞毒性淋巴细胞的浸润和效应功能，基于CD 8 + T细胞浸润与多种癌症中的反应率的强临床相关性，以及来自可植入小鼠肿瘤模型的功能作用的支持性证据。因此，在化疗期间增强CD 8 + T细胞应答有可能提高病理完全缓解率并延长患者生存期。我们最近使用转基因小鼠乳腺癌模型证明，肿瘤相关巨噬细胞消除化疗期间的CD 8 + T细胞依赖性反应。在未发表的工作中，我们现在已经确定这种抑制活性源自白细胞介素10（IL 10）的产生，因为巨噬细胞是肿瘤内白细胞介素10的主要来源，并且IL 10受体（IL 10 R）阻断剂在化疗反应期间模仿巨噬细胞拮抗剂的作用。虽然白细胞介素10不直接抑制CD 8 + T细胞增殖或功能，但我们观察到在联合化疗中用巨噬细胞拮抗剂治疗后肿瘤内树突状细胞浸润和白细胞介素12表达增加。因此，我们假设白细胞介素10抑制化疗诱导的细胞死亡后树突状细胞的活化，从而防止肿瘤内CD 8 + T细胞的再活化，并提供了一个易于处理的目标，以改善化疗期间的免疫反应。为了验证这些假设，我们提出了以下具体目标：确定肿瘤内树突状细胞活化在调节肿瘤生长中的功能意义。图1显示了在IL 10 R阻断后对化疗的应答的持续性;确定在IL 10 R阻断后肿瘤内与募集的CD 8 + T细胞在介导对化疗的应答中的功能贡献;以及比较在IL 10 R阻断和化疗与免疫检查点阻断的组合与共刺激激动剂后抗肿瘤免疫应答的持久性。