权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Ethanol Inhibition of anti-PD-1 Immunotherapy via T-cell Dysfunction and Intestinal Dysbiosis

乙醇通过 T 细胞功能障碍和肠道菌群失调抑制抗 PD-1 免疫治疗

基本信息

批准号：
10218700
负责人：
Leon Garland Coleman
金额：
$ 21.75万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-10 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218700
关键词：
16S ribosomal RNA sequencing Alcohol abuse Alcohol consumption Alcohols American Society of Clinical Oncology Bacteria Bifidobacterium Biometry Blood CD8B1 gene Cancer Model Cell Count Chronic Clinical Dose Environmental Risk Factor Ethanol Etiology Flow Cytometry Functional disorder Goals Immune Immune response Immunocompetent Immunohistochemistry Immunologic Factors Immunology Immunosuppression Immunotherapy Impairment In Vitro Infiltration Intestinal permeability Intestines Knowledge Ligands Link MC38 Malignant Neoplasms Measures Mediating Microbe Minority Modeling Monoclonal Antibodies Mus Patients Peripheral Population RNA, Ribosomal, 16S Reaction Time Role Sampling T cell response T-Cell Activation T-Lymphocyte Testing Tumor-infiltrating immune cells Volatile Fatty Acids alcohol effect alcohol exposure anti-PD-1 anti-PD1 antibodies anti-PD1 therapy cancer immunotherapy cancer therapy chemokine cytokine dysbiosis effective therapy genome sequencing gut microbiome gut microbiota immune function improved insight microbiome microbiome composition mortality neoantigens neoplastic cell patient response prevent programmed cell death protein 1 receptor response tool tumor tumor growth tumor microenvironment whole genome

项目摘要

Project Summary/Abstract Chronic alcohol (i.e. ethanol) has been linked to the etiology of several cancers1-3, however, to date there is almost no knowledge regarding the effects of alcohol exposure on responses to immunotherapy. Ethanol abuse disrupts immune function, which could specifically impact immunotherapy responses in several cancers. This prompted the American Society of Clinical Oncology to call for studies into the impact of chronic ethanol on immunotherapy4. We find that chronic ethanol reduces anti-PD-1 efficacy and causes intestinal dysbiosis during tumor growth in a manner that may reduce responses to anti-PD-1. Our central hypothesis is that ethanol impairs efficacy of anti-PD-1 therapy in multiple tumor types via dysregulation of T cell activation and tumor ingress. We hypothesize ethanol-induced intestinal dysbiosis contributes to this dysfunction. PD-1 receptor targeted immunotherapy has emerged as an effective treatment for a variety of advanced malignancies in a subset of responsive patients5. Tumor-induced PD-1 ligands suppress T-cell responses as a means of immune invasion to promote tumor growth5-7. Anti-PD-1 monoclonal antibodies (αPD-1 mAbs) can reverse PD-1 immunosuppression to facilitate tumor clearance in responsive patients. However, despite these exciting clinical results, only a minority of patients respond to anti-PD-1 therapy. Anti-PD-1 efficacy can be influenced by immunological factors such as T cell invasion into the tumor8 and environmental factors such as intestinal microbiota composition. Chronic ethanol use increases gut permeability, alters peripheral cytokines9, alters T-cell numbers and function10, and causes intestinal dysbiosis11-13, with multiple bacterial species depleted in ethanol models involved in response to αPD-1 mAbs11,12,14-18. Most of these bacteria are short-chain fatty acid (SCFA) producers that promote T-cell responses19,20 21,22. We assessed the effect of chronic ethanol on PD-1 immunotherapy in our established anti-PD-1 responsive murine immunocompetent BBN963 cancer model23. We found that chronic ethanol-treated mice (5 weeks) had substantially increased tumor growth and higher mortality than αPD-1 mAb treatment alone (100% survival in vehicle + anti-PD-1 vs 33% survival in Ethanol + anti-PD-1), with no effect of ethanol on tumor growth without αPD-1. Ethanol-treated mice showed alterations in peripheral and tumoral T-cell populations. Further, we found that during tumor growth chronic ethanol depletes Bifidobacterium, which is associated with positive responses to anti-PD-1 immunotherapy15. We hypothesize that ethanol impairs anti-PD-1 efficacy by disrupting T cell responses to tumor growth that involves alterations in intestinal microbiome composition. To test this hypothesis we propose to investigate the effect of ethanol on T- cell tumor infiltration and tumoricidal activity (Aim 1) and to study the role ethanol-induced intestinal dysbiosis in the loss of anti-PD-1 efficacy (Aim 2).

项目总结/文摘