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).

项目摘要/摘要 慢性酒精(即酒精)已被认为与几种癌症的病因有关1-3然而，到目前为止 几乎对酒精暴露对免疫治疗反应的影响一无所知。酒精滥用 扰乱免疫功能，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对慢性酒精对 4.免疫疗法。我们发现，慢性乙醇降低了抗PD-1的效果，并导致肠道生态失调 肿瘤生长的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治疗通过调节T细胞活化和肿瘤侵袭对多种肿瘤类型的疗效我们 假设乙醇引起的肠道生物失调是这种功能障碍的原因。 PD-1受体靶向免疫治疗已成为多种晚期肿瘤的有效治疗手段。 反应性患者亚组中的恶性肿瘤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单抗(αPD-1单抗)可以 逆转PD-1免疫抑制以促进有反应的患者的肿瘤清除。然而，尽管如此， 令人振奋的临床结果是，只有少数患者对抗PD-1治疗有反应。抗PD-1的疗效可以 受免疫因素的影响，如T细胞对肿瘤的侵袭8和环境因素，如 肠道微生物区系组成。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细胞的数量和功能10，并导致肠道生态失调11-13，多种细菌种类耗尽 在乙醇模型中，参与了对αPD-1mAbs11、12、14-18的反应。这些细菌大多是短链脂肪酸 (SCFA)促进T细胞应答的生产者19、20、21、22。我们评估了慢性乙醇对PD-1的影响 我们已建立的抗PD-1反应性小鼠免疫活性BBN963肿瘤模型的免疫治疗23。我们 发现长期酒精处理的小鼠(5周)显著增加了肿瘤生长和更高的死亡率 与αPD-1单抗单独治疗相比(赋形剂+抗PD-1组存活率为100%，乙醇+抗PD-1组存活率为33%)， 不含αPD-1的乙醇对肿瘤生长无影响。乙醇处理的小鼠外周血中出现变化 和肿瘤T细胞群。此外，我们发现，在肿瘤生长过程中，慢性乙醇会耗尽 双歧杆菌，这与抗PD-1免疫治疗的阳性反应有关。我们假设 乙醇通过破坏T细胞对肿瘤生长的反应而削弱抗PD-1的效果，这种反应涉及到 肠道微生物群组成。为了验证这一假说，我们建议研究乙醇对T- 肿瘤细胞的侵袭和杀瘤活性(目标1)，并研究乙醇诱导的肠道菌群失调的作用 抗PD-1药效丧失(目标2)。