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Beta-adrenergic mediated suppression of T cell chemotaxis by cancers

β-肾上腺素能介导的癌症对 T 细胞趋化性的抑制

基本信息

批准号：
9306460
负责人：
DAVID W. MULLINS
金额：
$ 8.1万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306460
关键词：
Adoptive Immunotherapy Adoptive Transfer Adrenergic Agents Adrenergic beta-Agonists Adrenergic beta-Antagonists CCR CD8-Positive T-Lymphocytes CD8B1 gene CXCL10 gene CXCL11 gene CXCL9 gene CXCR3 gene Cancer Vaccines Cells Chemotaxis Chronic Clinical Colon Data Development Evaluation Exploratory/Developmental Grant Foundations Future Generations Growth Housing Immune Immune response Immunologics Immunosuppression Immunotherapy Infiltration Interferon Type II Interferons Investigation Maintenance Malignant Neoplasms Mediating Modeling Molecular Mus National Cancer Institute Nature Neoplasm Metastasis Norepinephrine Organ Patients Pharmacology Phase Play Process Production Proxy Regulation Reporting Role Roswell Park Cancer Institute Sampling Signal Pathway Signal Transduction Solid Solid Neoplasm Stress System T cell therapy T-Lymphocyte Temperature Therapeutic Translating Tumor Antigens Tumor Immunity Tumor-Derived Vaccines adrenergic block base cancer immunotherapy cancer therapy chemokine chemokine receptor clinically relevant combinatorial conditioning experience improved inhibitor/antagonist melanoma mouse model novel outcome forecast pre-clinical preclinical study receptor restoration trafficking tumor tumor growth tumor microenvironment

项目摘要

ABSTRACT Tumor growth induces local and systemic immunosuppressive effects that diminish immune cell infiltrationoftumors,therebylimitingtheefficacyofTcell-basedimmunotherapies.Wepreviously demonstrated that restoration of interferon signaling and downstream expression of CXCR3 cognate chemokines is sufficient to restore T cell infiltration of tumors. However, the mechanisms that modulate chemokine production and T cell infiltration in tumors remain poorly defined. Recent studies have reported that mice maintained at standard vivarium temperatures (ST conditions, ~24°C) experience chronic cold stress and induction of -adrenergic signaling, including induction of high levels of circulating norepinephrine (NE), relative to mice maintained in thermoneutral (TN) conditions (28-30°C). Significantly, tumors grow more rapidly in ST- conditioned mice, concurrent with reduced CD8 infiltration and chemokine production. Thus, tumors in ST mice immunologically resemble patient-derived samples (NE replete and lacking chemokine and T cell infiltrates), suggesting that stress-induced signaling pathways may play a major role in limiting immune responses to tumors. We propose that -adrenergic signaling suppresses interferon and interferon-inducible chemokine production (including CXCR3-cognate chemokines CXCL9 and CXCL10) in the tumor microenvironment, thereby limiting CXCR3+CD8 T cell infiltration and immune-mediated tumor rejection. By extension, blocking -adrenergic signaling may induce or restore interferon-inducible chemokine production and CXCR3+ T cell infiltration in tumors. In this exploratory/developmental study, we will 1) investigate the role of - adrenergic signaling in regulation of chemokine production and T cell trafficking to the melanoma microenvironment; and 2) assess the impact of -adrenergic signaling on T cell-based therapies for cancer. These studies will inform future R01-scale investigations of the specific molecular and cellular mechanisms of action in stress-mediated changes in the tumor microenvironment, and provide a conceptual basis to translate these preclinical studies into clinical Phase 0/1 trials that combine -blockers and cancer immunotherapy for the purpose of enhancing T cell infiltration and anti-tumor efficacy.

摘要