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
• 负责人: Leon Garland Coleman
• 金额: $ 18.47万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-10 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403618
• 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

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).

项目概要/摘要 长期饮酒（即乙醇）与多种癌症的病因有关1-3，然而，迄今为止， 几乎不知道酒精暴露对免疫治疗反应的影响。滥用乙醇 破坏免疫功能，这可能会特别影响几种癌症的免疫治疗反应。这 促使美国临床肿瘤学会呼吁研究长期乙醇对健康的影响 免疫治疗4.我们发现长期摄入乙醇会降低抗 PD-1 功效并导致肠道菌群失调 肿瘤的生长方式可能会降低对抗 PD-1 的反应。我们的中心假设是乙醇会损害 抗 PD-1 疗法通过 T 细胞活化和肿瘤进入失调对多种肿瘤类型的疗效。我们 假设乙醇引起的肠道菌群失调导致了这种功能障碍。 PD-1受体靶向免疫治疗已成为治疗多种晚期疾病的有效方法 一部分有反应的患者患有恶性肿瘤5。肿瘤诱导的 PD-1 配体抑制 T 细胞反应 免疫侵袭手段促进肿瘤生长5-7．抗 PD-1 单克隆抗体 (αPD-1 mAb) 可以 逆转 PD-1 免疫抑制，促进有反应的患者的肿瘤清除。然而，尽管有这些 令人兴奋的临床结果是，只有少数患者对抗 PD-1 治疗有反应。抗PD-1功效可 受免疫因素（例如 T 细胞侵入肿瘤）和环境因素（例如 肠道微生物群的组成。长期使用乙醇会增加肠道通透性，改变外周细胞因子9， 改变 T 细胞数量和功能10，并导致肠道菌群失调11-13，多种细菌种类被耗尽 在涉及 αPD-1 mAbs11,12,14-18 反应的乙醇模型中。这些细菌大部分都是短链脂肪酸 (SCFA) 促进 T 细胞反应的生产者19,20 21,22。我们评估了长期乙醇对 PD-1 的影响 我们建立的抗 PD-1 反应性小鼠免疫活性 BBN963 癌症模型中的免疫疗法23。我们 发现长期接受乙醇治疗的小鼠（5周）肿瘤生长显着增加，死亡率更高 与单独使用 αPD-1 mAb 治疗相比（载体 + 抗 PD-1 存活率为 100%，乙醇 + 抗 PD-1 存活率为 33%）， 在没有 αPD-1 的情况下，乙醇对肿瘤生长没有影响。乙醇处理的小鼠显示出外周血的改变 和肿瘤 T 细胞群。此外，我们发现在肿瘤生长过程中，慢性乙醇消耗 双歧杆菌，与抗 PD-1 免疫疗法的阳性反应相关15。我们假设 乙醇通过破坏 T 细胞对肿瘤生长的反应来损害抗 PD-1 功效，其中涉及改变 肠道微生物组的组成。为了检验这一假设，我们建议研究乙醇对 T-的影响 细胞肿瘤浸润和杀肿瘤活性（目标 1），并研究乙醇诱导的肠道菌群失调在 抗 PD-1 功效丧失（目标 2）。