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:
- 金额:$ 21.75万
- 依托单位:
- 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:
- 关键词:16S ribosomal RNA sequencingAlcohol abuseAlcohol consumptionAlcoholsAmerican Society of Clinical OncologyBacteriaBifidobacteriumBiometryBloodCD8B1 geneCancer ModelCell CountChronicClinicalDoseEnvironmental Risk FactorEthanolEtiologyFlow CytometryFunctional disorderGoalsImmuneImmune responseImmunocompetentImmunohistochemistryImmunologic FactorsImmunologyImmunosuppressionImmunotherapyImpairmentIn VitroInfiltrationIntestinal permeabilityIntestinesKnowledgeLigandsLinkMC38Malignant NeoplasmsMeasuresMediatingMicrobeMinorityModelingMonoclonal AntibodiesMusPatientsPeripheralPopulationRNA, Ribosomal, 16SReaction TimeRoleSamplingT cell responseT-Cell ActivationT-LymphocyteTestingTumor-infiltrating immune cellsVolatile Fatty Acidsalcohol effectalcohol exposureanti-PD-1anti-PD1 antibodiesanti-PD1 therapycancer immunotherapycancer therapychemokinecytokinedysbiosiseffective therapygenome sequencinggut microbiomegut microbiotaimmune functionimprovedinsightmicrobiomemicrobiome compositionmortalityneoantigensneoplastic cellpatient responsepreventprogrammed cell death protein 1receptorresponsetooltumortumor growthtumor microenvironmentwhole 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
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Leon Garland Coleman其他文献
Leon Garland Coleman的其他文献
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{{ 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:
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