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: 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
• 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

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/摘要 慢性酒精（即乙醇）与几种癌症的病因有关1 -3，然而，迄今为止， 几乎没有关于酒精暴露对免疫治疗反应的影响的知识。乙醇滥用 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慢性乙醇对 免疫疗法4.我们发现，慢性乙醇降低抗PD-1的疗效，并导致肠道生态失调， 肿瘤生长的方式，可能会减少对抗PD-1的反应。我们的中心假设是乙醇损害了 通过T细胞活化和肿瘤侵入的失调，抗PD-1疗法在多种肿瘤类型中的功效。我们 假设乙醇诱导肠生态失调促成了这种功能障碍。 PD-1受体靶向免疫治疗已成为各种晚期肿瘤的有效治疗方法。 恶性肿瘤在一个子集的反应patients 5.肿瘤诱导的PD-1配体抑制T细胞应答， 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 逆转PD-1免疫抑制以促进应答患者的肿瘤清除。然而，尽管有这些 尽管有令人兴奋的临床结果，但只有少数患者对抗PD-1治疗有反应。抗PD-1功效可以是 受免疫因素如T细胞侵入肿瘤8和环境因素如 肠道微生物群组成。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，导致肠道生态失调11 -13，多种细菌种类耗尽 参与对αPD-1 mAbs反应的乙醇模型11，12，14-18。这些细菌大多是短链脂肪酸 （SCFA）生产商，促进T细胞反应19，20 21，22。我们评估了慢性乙醇对PD-1的影响， 在我们建立的抗PD-1应答性鼠免疫活性BBN 963癌症模型中的免疫疗法23。我们 发现长期乙醇处理小鼠（5周）的肿瘤生长大幅增加，死亡率更高 与单独的αPD-1 mAb治疗相比（溶媒+抗PD-1中100%存活率vs乙醇+抗PD-1中33%存活率）， 在没有αPD-1的情况下，乙醇对肿瘤生长没有影响。乙醇处理的小鼠表现出外周血淋巴细胞的变化， 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而损害抗PD-1功效， 肠道微生物组组成。为了验证这一假设，我们建议研究乙醇对T- 细胞肿瘤浸润和杀肿瘤活性（目的1），并研究乙醇诱导的肠道生态失调在 抗PD-1疗效的丧失（目的2）。