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

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Leon Garland Coleman其他文献

Leon Garland Coleman的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Leon Garland Coleman', 18)}}的其他基金

Scientific Mentoring and Research Experiences Core
科学指导和研究经验核心
  • 批准号:
    10541712
  • 财政年份:
    2022
  • 资助金额:
    $ 21.75万
  • 项目类别:
Scientific Mentoring and Research Experiences Core
科学指导和研究经验核心
  • 批准号:
    10705747
  • 财政年份:
    2022
  • 资助金额:
    $ 21.75万
  • 项目类别:
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
  • 批准号:
    10403618
  • 财政年份:
    2021
  • 资助金额:
    $ 21.75万
  • 项目类别:
Ethanol modulate central and peripheral immune responses via HMGB1, IL-1Beta, and other Immune Signaling Molecules
乙醇通过 HMGB1、IL-1Beta 和其他免疫信号分子调节中枢和外周免疫反应
  • 批准号:
    9314186
  • 财政年份:
    2017
  • 资助金额:
    $ 21.75万
  • 项目类别:
Ethanol modulate central and peripheral immune responses via HMGB1, IL-1Beta, and other Immune Signaling Molecules
乙醇通过 HMGB1、IL-1Beta 和其他免疫信号分子调节中枢和外周免疫反应
  • 批准号:
    10004214
  • 财政年份:
    2017
  • 资助金额:
    $ 21.75万
  • 项目类别:
Ethanol modulate central and peripheral immune responses via HMGB1, IL-1Beta, and other Immune Signaling Molecules
乙醇通过 HMGB1、IL-1Beta 和其他免疫信号分子调节中枢和外周免疫反应
  • 批准号:
    9757591
  • 财政年份:
    2017
  • 资助金额:
    $ 21.75万
  • 项目类别:
Ethanol modulate central and peripheral immune responses via HMGB1, IL-1Beta, and other Immune Signaling Molecules
乙醇通过 HMGB1、IL-1Beta 和其他免疫信号分子调节中枢和外周免疫反应
  • 批准号:
    10238811
  • 财政年份:
    2017
  • 资助金额:
    $ 21.75万
  • 项目类别:
Alcohol and Development of the Prefrontal Cortex
酒精与前额皮质的发育
  • 批准号:
    7755831
  • 财政年份:
    2008
  • 资助金额:
    $ 21.75万
  • 项目类别:
Alcohol and Development of the Prefrontal Cortex
酒精与前额皮质的发育
  • 批准号:
    7923681
  • 财政年份:
    2008
  • 资助金额:
    $ 21.75万
  • 项目类别:
Alcohol and Development of the Prefrontal Cortex
酒精与前额皮质的发育
  • 批准号:
    8135956
  • 财政年份:
    2008
  • 资助金额:
    $ 21.75万
  • 项目类别:

相似海外基金

Insula-amygdala circuits in alcohol abuse
酒精滥用中的岛杏仁核回路
  • 批准号:
    10735851
  • 财政年份:
    2023
  • 资助金额:
    $ 21.75万
  • 项目类别:
A novel animal model to study the association between alcohol abuse during late adolescence with common conditions observed in combat Veterans
一种新的动物模型,用于研究青春期后期酗酒与退伍军人中观察到的常见状况之间的关联
  • 批准号:
    10644999
  • 财政年份:
    2022
  • 资助金额:
    $ 21.75万
  • 项目类别:
Reinforcement as a Prospective Predictor of Real-time Alcohol Abuse Following Bariatric Surgery
强化作为减肥手术后实时酒精滥用的前瞻性预测因子
  • 批准号:
    10370120
  • 财政年份:
    2022
  • 资助金额:
    $ 21.75万
  • 项目类别:
ACSS2 inhibition in treating Alcohol Abuse
ACSS2 抑制治疗酒精滥用
  • 批准号:
    10546942
  • 财政年份:
    2022
  • 资助金额:
    $ 21.75万
  • 项目类别:
A novel animal model to study the association between alcohol abuse during late adolescence with common conditions observed in combat Veterans
一种新的动物模型,用于研究青春期后期酗酒与退伍军人中观察到的常见状况之间的关联
  • 批准号:
    10368295
  • 财政年份:
    2022
  • 资助金额:
    $ 21.75万
  • 项目类别:
Reinforcement as a Prospective Predictor of Real-time Alcohol Abuse Following Bariatric Surgery
强化作为减肥手术后实时酒精滥用的前瞻性预测因子
  • 批准号:
    10705563
  • 财政年份:
    2022
  • 资助金额:
    $ 21.75万
  • 项目类别:
The Functional Implications of Astrocytic GPCR-signaling on Alcohol Abuse
星形胶质细胞 GPCR 信号传导对酒精滥用的功能影响
  • 批准号:
    10472456
  • 财政年份:
    2021
  • 资助金额:
    $ 21.75万
  • 项目类别:
Trauma and Neurobiological Threat Reactivity as Risk Factors for Alcohol Abuse in Youth
创伤和神经生物学威胁反应作为青少年酗酒的危险因素
  • 批准号:
    10582520
  • 财政年份:
    2021
  • 资助金额:
    $ 21.75万
  • 项目类别:
Trauma and Neurobiological Threat Reactivity as Risk Factors for Alcohol Abuse in Youth
创伤和神经生物学威胁反应作为青少年酗酒的危险因素
  • 批准号:
    10368089
  • 财政年份:
    2021
  • 资助金额:
    $ 21.75万
  • 项目类别:
The Functional Implications of Astrocytic GPCR-signaling on Alcohol Abuse
星形胶质细胞 GPCR 信号传导对酒精滥用的功能影响
  • 批准号:
    10089613
  • 财政年份:
    2021
  • 资助金额:
    $ 21.75万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了