肠道微生物与免疫检查点阻断剂相互作用机制的研究进展

随着免疫治疗2.0时代的到来,免疫检查点阻断剂(ICIs)已成为多种类型肿瘤治疗的新选择。多项研究表明,肿瘤患者肠道微生物与ICIs治疗反应密切相关,肠道微生物通过易位、免疫调节、代谢、酶促降解和多样性变异影响ICIs的疗效。此外,ICIs在改变肠道微生物组成和减少细菌多样性的同时,增加了胃肠道免疫相关不良反应。肠道微生物在预测ICIs疗效及免疫毒性方面有其独特的临床价值,故对应用ICIs的肿瘤患者进行肠道微生物分析已成为一种潜在需求。本综述主要介绍肠道微生物与ICIs相互作用机制的最新研究进展,以便更好地识别ICIs的应答者并提高其疗效和安全性。     

活菌药物在肿瘤免疫治疗中的应用进展和未来展望

肠道微生物是人体重要的器官，在人类健康和疾病中发挥重要作用。很多疾病被证实与肠道微生物的组成和功能 改变相关。肿瘤免疫治疗作为一种新兴的肿瘤治疗手段，具有特异性强、疗效显著等特点，免疫检查点抑制剂是目前应用较为 广泛的方法之一。免疫检测点抑制剂的疗效与肠道菌群有直接联系。本文对近年来肿瘤免疫治疗相关肠道微生物的研究进 展进行总结，阐述了肠道菌群在肿瘤治疗中的功能和作用机制，如通过代谢产物或表面蛋白直接或间接抑制肿瘤生长或诱导 肿瘤细胞凋亡，调节免疫系统特别是肿瘤微环境发挥抗肿瘤功能等。随着HUMAnN2流程、DADA2流程、metaWRAP等生物信 息工具和统计方法在肠道菌群方面的应用，肠道菌群在肿瘤免疫方面的研究得到进一步发展。目前，各研究机构和生物制药 公司均已在肠道微生物领域进行规划，并已注册多项临床试验。本文还就免疫治疗相关肠道微生物的发现方法以及用于肿瘤 免疫治疗的活菌药物开发进展情况进行介绍，并在此基础上探讨了目前的缺陷和未来的发展趋势。     

调节肿瘤免疫治疗的靶点：肠道菌群

摘 要：免疫检查点抑制剂成为多种恶性肿瘤重要的治疗方法,可显著改善肿瘤患者的总生存,然而相当一部分接受免疫检查点抑制剂治疗的患者不能获益。越来越多的证据表明肠道菌群与肿瘤免疫治疗的疗效和不良反应相关,有目的地调整肠道菌群使免疫治疗有益菌富集,有望成为提高免疫治疗疗效的手段。各类研究中影响免疫治疗疗效的肠道菌群种属只有少量重叠,本文就近几年与肿瘤免疫治疗相关的几种肠道菌群进行综述。     

肠道菌群与肿瘤免疫治疗疗效及不良反应关系的研究进展

肠道菌群是寄生于肠道内微生物的总称。肠道菌群受到宿主饮食和药物等多种因素影响,同时,肠道菌群也可以参与调控宿主免疫状态。目前,已有一些研究证实了肠道菌群与抗肿瘤免疫治疗疗效及不良反应具有相关性,且调节肠道菌群可以提升免疫治疗疗效,但是具体的机制尚不清楚。本文对肠道菌群与肿瘤免疫治疗现有的研究进展及不足进行了系统综述。     

肠道菌群影响肿瘤对免疫检查点抑制剂的应答及其机制

人类肠道菌群种类超过1000种,是人体内最庞大的微生物群,被称为"被遗忘的器官"。肠道菌群易受多种因素影响。已有多项研究证明肠道菌群及其代谢产物参与宿主免疫构建和影响肿瘤微环境,与肿瘤对免疫检查点抑制剂(immune checkpoint inhibitor,ICI)的应答和ICI治疗相关不良反应的发生有关。随着人类微生物组计划的开展和测序分析技术的进步,肠道菌群的相关研究逐步深入,基因功能注释和代谢组学分析的成熟和推广丰富了肠道菌群与宿主免疫及免疫治疗间的探索维度,干预和塑造肠道菌群为提高肿瘤免疫治疗效果提供了新的思路。然而,微生物制品的食源性添加、粪菌移植等研究尚未获得足够证据,肠道菌群的免疫调控机制尚不完全清楚。本文就近年来肠道菌群影响肿瘤对ICI应答机制的研究进展作一综述。     

肠道菌群在肿瘤免疫治疗中的作用研究进展

肠道微生物与肿瘤发生、发展关系密切。机体暴露于大量肠道菌群及其代谢产物中,构成机体的生态环境,肠道微生物通过多种途径参与肿瘤的发生与发展。肠道菌群在肿瘤的治疗中发挥重要作用。目前,肿瘤免疫检测点抑制剂在多种恶性肿瘤中的治疗取得重要突破,肠道微生物组对肿瘤免疫治疗,尤其是免疫检测点抑制剂的疗效产生重要影响。本文就近年来肠道菌群对肿瘤免疫治疗中的作用及影响展开综述,为免疫检测点抑制剂在肿瘤治疗中的应用提供参考。      

抗生素在肿瘤发生发展及免疫治疗中的作用

近年来,以免疫检查点抑制剂(ICI)为代表性药物的肿瘤免疫治疗成为晚期恶性肿瘤重要的治疗方法。临床前研究发现,肠道微生物群紊乱会降低应用ICI患者的临床获益。最新的数据表明,抗生素可能通过改变肠道微生物群的丰度及组成进一步影响肿瘤的发生发展及免疫治疗疗效。总结抗生素在晚期恶性肿瘤免疫治疗中的作用,可为优化晚期肿瘤患者治...     

肠道菌群和免疫检查点抑制剂治疗关系研究进展

近年来，肠道菌群在免疫检查点抑制剂（immune checkpoint inhibitors，ICI）治疗中的地位得到广泛认可，是当前免疫治疗的研究热点之一。肠道菌群可通过促进机体免疫系统发育，塑造肿瘤免疫环境，并且可能关联其他免疫生物标志物如肿瘤突变负荷、肿瘤新生抗原、微卫星不稳定，影响ICI治疗最终疗效。因此，通过对肠道菌群准确有效的干预，提高免疫治疗的疗效成为肠道菌群临床转化研究的重点。目前以肠道菌群为治疗靶点，借助抗生素、粪便移植、口服益生菌等手段来提高ICI疗效，减少免疫相关不良反应的治疗方式值得深入研究，但临床仍面临较多问题。为此，本文就肠道菌群与ICI治疗间的关系进行综述。      

肠道菌群影响肿瘤免疫治疗的机制及临床应用研究进展

肿瘤免疫治疗是继手术、化疗、放疗后的第四种疗法，在部分上皮性肿瘤和血液性肿瘤的治疗中取得较大突破，但不良反应常见甚至比较严重，在部分实体肿瘤中的应答率也不够理想。随着基因组学和代谢组学技术的成熟，人们逐渐认识到肠道菌群在肿瘤发展与治疗中的作用。菌群可能通过调节宿主免疫系统和肿瘤微环境等方式影响肿瘤免疫，部分细菌通过激活免疫起到协助对抗肿瘤的作用，而有些细菌则介导免疫抑制帮助癌细胞逃避免疫系统的杀伤。越来越多的研究揭示肿瘤免疫治疗的效果和并发症与患者肠道菌群组成有关，对治疗敏感或易发生不良反应的患者肠道菌群组成有一定特征。这些特征可能作为生物标志物来预测免疫治疗的预后，也可能被开发为“免疫增效剂”（如Akk菌和双歧杆菌）来辅助免疫治疗。部分临床和临床前研究已证明包括菌群移植在内的微生物干预能一定程度上提高免疫治疗的敏感性或减轻不良反应。随着基因编辑技术和纳米技术的发展，有助于免疫治疗的工程细菌的设计开发成为了新的研究热点。基于肠道菌群和免疫治疗的关系，正确挖掘微生物信息、开发合理可行的微生物干预手段，有希望在很大程度上优化肿瘤免疫疗法，为肿瘤治疗带来新的突破。     

肠道微生物群与免疫治疗疗效的关系

摘 要：肠道微生物群是一个极其复杂的群体,因其重要的作用被认为是人体器官或人类的“第二基因组”。肠道微生物群不仅与肠道免疫的关系密切,而且影响了全身免疫系统。近年的研究显示,肠道微生物群可以影响免疫治疗疗效。由于可能导致肠道微生物群失调,因此在接受免疫检查点抑制剂（ICIs）治疗前后应尽量避免使用抗生素;此外,对部分患者进行粪便移植有望提高免疫治疗疗效。基于上述原因,管理肠道微生物群也成为了免疫治疗管理的一个重要内容,肠道微生物群有望成为一个潜在的预测免疫治疗疗效的生物标志物。     

免疫检查点抑制剂治疗结直肠癌的疗效及肠道菌群对其疗效影响的研究进展

随着免疫治疗领域的快速发展,越来越多的免疫检查点抑制剂被应用于临床。免疫治疗为结直肠癌晚期转移患者提供了一种新的治疗选择。研究证实,错配修复缺陷/高度微卫星不稳定（dMMR/MSI-H）状态的晚期转移性结直肠癌患者对免疫治疗更敏感,有较为客观及持续的临床反应。在肿瘤免疫治疗的应答中,肠道菌群被证实有一定的调节作用,部分细菌可通过免疫系统或机体代谢功能来影响免疫检查点抑制剂的疗效。随着研究的进展,肠道菌群不仅有望成为结直肠癌免疫治疗的疗效预测性生物标志物,也可能成为影响结直肠癌免疫治疗结果的关键调控因素,在今后的临床治疗中,为更多的晚期结直肠癌患者使用免疫检查点抑制剂获益带来可能性。     

Immuno-oncology-microbiome axis of gastrointestinal malignancy

Research on the relationship between the microbiome and cancer has been controversial for centuries. Recent works have discovered that the intratumor microbiome is an important component of the tumor microenvironment (TME). Intratumor bacteria, the most studied intratumor microbiome, are mainly localized in tumor cells and immune cells. As the largest bacterial reservoir in human body, the gut microbiome may be one of the sources of the intratumor microbiome in gastrointestinal malignancies. An increasing number of studies have shown that the gut and intratumor microbiome play an important role in regulating the immune tone of tumors. Moreover, it has been recently proposed that the gut and intratumor microbiome can influence tumor progression by modulating host metabolism and the immune and immune tone of the TME, which is defined as the immuno-oncology-microbiome (IOM) axis. The proposal of the IOM axis provides a new target for the tumor microbiome and tumor immunity. This review aims to reveal the mechanism and progress of the gut and intratumor microbiome in gastrointestinal malignancies such as esophageal cancer, gastric cancer, liver cancer, colorectal cancer and pancreatic cancer by exploring the IOM axis. Providing new insights into the research related to gastrointestinal malignancies.     

Implication of gut microbiome in immunotherapy for colorectal cancer

Colorectal cancer (CRC) constitutes the third most frequently reported malignancy in the male population and the second most common in women in the last two decades. Colon carcinogenesis is a complex, multifactorial event, resulting from genetic and epigenetic aberrations, the impact of environmental factors, as well as the disturbance of the gut microbial ecosystem. The relationship between the intestinal microbiome and carcinogenesis was relatively undervalued in the last decade. However, its remarkable effect on metabolic and immune functions on the host has been in the spotlight as of recent years. There is a strong relationship between gut microbiome dysbiosis, bowel pathogenicity and responsiveness to anti-cancer treatment; including immunotherapy. Modifications of bacteriome consistency are closely associated with the immunologic response to immunotherapeutic agents. This condition that implies the necessity of gut microbiome manipulation. Thus, creatingan optimal response for CRC patients to immunotherapeutic agents. In this paper, we will review the current literature observing how gut microbiota influence the response of immunotherapy on CRC patients.     

The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC

IntroductionGut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti–programmed death 1 (PD-1) blockade.MethodsThirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.ResultsWhen subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8⁺ T cell and natural killer cell subsets in the periphery in response to anti–PD-1 therapy.ConclusionsOur results reveal strong correlation between gut microbiome diversity and the responses to anti–PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti–PD-1 immunotherapy against NSCLC in the Chinese population.     

The Role of the Gut Microbiome in Colorectal Cancer: Where Are We? Where Are We Going?

Microbiome (microbiota) is a community of all microorganisms inhabiting a specific site of the body, including pathogens, which distinguishes it from the physiological microflora. Intestinal dysbiosis plays a key role in the development of colorectal cancer. In the process of carcinogenesis, inflammation, immune response, and toxic metabolites play a significant role. Specific species of bacteria might affect the risk of colorectal cancer and growth of tumor already present. Assessment of changes in the intestinal microbiome during the development and progression of colorectal cancer might create a simple diagnostic tool, a useful biomarker, or might influence treatment strategies in colorectal cancer patients. Analysis of the gut microbiome provides the potential to develop noninvasive diagnostic tests that would be useful as new protective markers of colorectal cancer, prognostic markers in already present colorectal cancer, and predictive markers of response to treatment, especially immunotherapy.     

The interaction between gut microbiome and anti-tumor drug therapy

A large number of symbiotic gut microbiome exists in the human gastrointestinal micro-ecosystem. The daily diet, lifestyle, and body constitution influence the type and quantity of gut microbiome in the body. Increasing evidence demonstrates that the gut microbiome can affect tumor development and progress. We discuss in this paper how the gut microbiome impacts tumor pathology through DNA damage, production of dietary and microbial metabolites, altered cellular signaling pathways, immune system suppression, and involvement in pro-inflammatory pathways changing gut microbiome composition. The gut microbiome acts on different types of the anti-tumor drug through bacterial translocation, immuno-modulation, metabolic modulation, enzymatic degradation, and reduction of microbial diversity. This article summarized the aforementioned by reviewing recent studies on the interaction among the gut microbiome, tumor development, and antitumor drugs.     

Temperature as a modulator of the gut microbiome: what are the implications and opportunities for thermal medicine?

Abstract

There is substantial research being conducted on the relationships between the gut microbiome, the immune response and health and disease. Environmental temperature and heat stress are known to modify the gut microbiome. Changes in core temperature have been linked, in multiple phyla, to altered microbiome composition and function. This raises the question of whether local/regional or whole body thermal therapies which target tumors in the abdomen, peritoneal cavity, or pelvis influence the gut microbiome. To date, there is little information on whether thermal therapy exerts positive or negative effects on the microbiome. This is an intriguing question since there is growing interest in the immunological impact of various thermal therapies. The goal of this brief review is to highlight research on how environmental conditions, particularly temperature (internal as well as external temperatures) influences the gut microbiome. Given the potential for temperature shifts to modulate gut microbe function and composition, it is likely that various forms of thermal therapy, including hyperthermic intraperitoneal chemotherapy (HIPEC), deep regional, and whole body hyperthermia influence the microbiome in ways that are currently not appreciated. More research is needed to determine whether thermal therapy induced changes in the microbiome occur, and whether they are beneficial or detrimental to the host. Currently, although approaches to microbiome modification such as dietary intervention, fecal transfer, probiotics and prebiotics are being developed, the potential of temperature manipulation has, as yet, not been explored. Therefore, new research could reveal whether perturbations of the microbiome composition that have negative health consequences (dysbiosis) could be an important target for treatment by thermal medicine.     

Pembrolizumab for the treatment of gastric cancer

Introduction: Gastric cancer is one of a few gastrointestinal malignancies in which immunotherapy has shown meaningful activity. Pembrolizumab is the first and only immune checkpoint inhibitor to be FDA-approved in gastric cancer.

Areas Covered: This review summarizes the current and emerging clinical evidence for immune checkpoint inhibitors in advanced and metastatic gastric cancer, with a focus on pembrolizumab.

Expert Commentary: Pembrolizumab has shown impressive activity in the third-line treatment of locally advanced and metastatic gastric cancer. It is currently being studied as upfront therapy in combination with chemotherapy. The emerging understanding of the molecular alterations and tumor immune microenvironment as predictors of immunotherapy response in gastric cancer are discussed. The impact of gastric mucosal dysbiosis on gastric carcinogenesis and the modulation of immunotherapy response by the gut microbiome are also reviewed.     

Crosstalk between gut microbiota and COVID-19 impacts pancreatic cancer progression

Pancreatic cancer (PC) is one of the most common causes of cancer-associated death worldwide, with a low rate of 5-year survival. Currently, the pathogenesis of PC is complicated, with no efficient therapy. Coronavirus disease 2019 (COVID-19) disease caused by severe acute respiratory syndrome coronavirus 2 further exacerbates the challenge of patients with PC. The alteration of gut microbiota caused by COVID-19 infection may impact PC progression in patients via immune regulation. The expression of inflammatory immune mediators such as interleukin (IL)-6, IL-8, and IL-10 has been found to increase in both PC and COVID-19 patients, which is associated with the disease severity and prognostic outcome. Gut microbiome serves as a critical connector between viral infection and PC. It can regulate host systemic immune response and impact the efficacy of immunotherapy. Here, we first demonstrated the features of inflammatory cytokines in both diseases and their impact on disease outcomes. Then, we demonstrated the importance of immunotherapeutic strategies. This includes the immune modulation that targets a single or dual receptors using a single agent or their combinations for the treatment of PC in patients who get infected with COVID-19. Additionally, we explored the possibility of managing the disease by regulating gut microbiome. Overall, modulation of the lung-gut-pancreases axis can boost anti-cancer immunotherapy and reduce adverse prognostic outcomes.