The microbiome and human cancer.
The microbiome and human cancer.
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DOI：
10.1126/science.abc4552
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发表时间：
2021-03-26
期刊：
影响因子：
--
通讯作者：
Knight R
中科院分区：
文献类型：
--
作者：
Sepich-Poore GD;Zitvogel L;Straussman R;Hasty J;Wargo JA;Knight R
将癌症和微生物联系起来的历史记载可以追溯到4000年前。在传染病的细菌理论建立后，微生物对癌症影响的临床研究开始于1868年，当时William Busch报告了化脓性链球菌感染患者的自发肿瘤消退。在接下来的世纪里，细菌在致癌和癌症治疗中的作用由于重现性差、错误的微生物声明和对患者的严重毒性而被低估。然而，这些提供了癌症免疫疗法的一些初步证明。与此同时，癌症的病毒理论开始蓬勃发展，受到1911年劳斯肉瘤病毒（RSV）发现的刺激，该病毒将家禽的良性组织转化为恶性肿瘤。随后长达数十年的寻找每一种人类癌症背后的病毒的努力最终失败了，许多癌症从根本上与体细胞突变有关。现在，该领域正在遇到有趣的主张，即微生物（包括细菌和真菌）在癌症和癌症治疗中的重要性。本评论根据现代癌症生物学和免疫学批判性地评估了这些说法的证据，并通过检查拟议机制、诊断、内源性调节方法和外源性治疗策略的最新进展来描绘微生物在癌症中的作用。很少有微生物直接导致癌症，但许多微生物似乎参与了癌症的生长，通常通过宿主的免疫系统起作用;相反，一些微生物具有免疫刺激特性。肠道微生物-免疫系统相互作用的机制分析已经证明，通过调节初级和次级淋巴组织对癌症和肿瘤免疫监视的活性，对先天性和适应性免疫具有强大的作用。许多这些途径调用Toll样受体（TLR）启动的细胞因子信号，但微生物代谢的饮食能量收获和短链脂肪酸的生产，和抗原模拟与癌细胞的影响，也很重要。在临床前模型中，微生物代谢物还调节肿瘤体细胞突变的表型并调节免疫检查点抑制剂的功效。新出现的证据也表明肿瘤内细菌的存在和功能活性，在~10种癌症类型中重叠免疫组织化学，免疫荧光，电子显微镜和测序数据。初步研究还表明，真菌和噬菌体有助于胃肠道癌症。然而，相对于癌细胞，肿瘤内微生物的估计细胞丰度较低，并且对其功能库和效力的了解仍然有限。需要在不同的队列和治疗背景下进一步验证其患病率和影响。宿主微生物群的免疫调节作用重新激发了改变其组成作为免疫疗法形式的努力。尽管有广泛的临床前证据，但将微生物群调节方法转化为人类尚未广泛实现商业化治疗。然而，合成生物学方法也在临床前和临床试验环境中获得了工程化细菌癌症疗法的牵引力。更好地了解微生物在癌症中的作用有机会改善癌症护理周期的每个阶段，但必须克服重大挑战。协调一致的努力来表征肿瘤，粪便和血液样本中的癌症相关微生物群与金标准污染控制将极大地有助于这一进展。这将类似于癌症基因组图谱（TCGA）和国际癌症基因组联盟（ICGC）在表征癌症体细胞突变景观中的作用。大规模的临床试验目前正在测试微生物群调节方法的功效，从饮食调整到肿瘤内注射工程细菌。这些细菌癌症疗法，如果安全有效，可以极大地扩大癌症治疗的医疗设备。总而言之，整合以宿主为中心的癌症和微生物的观点可能会改善患者的预后，同时提供对癌症宿主微生物进化的细致入微的理解。微生物影响癌症护理的机会。诊断：癌症特异性，血液传播的微生物DNA可以补充无细胞肿瘤DNA（ctDNA）。预后：肠道和肿瘤内微生物群可能对患者结局进行分层;（N）R=（无）应答者; TME=肿瘤微环境。治疗：瘤内注射产生CD 47纳米抗体（CD 47 nb）的E.大肠杆菌可以通过增强树突状细胞（DC）吞噬、淋巴结（LN）抗原（Ag）呈递和细胞毒性T淋巴细胞（CTL）活性来产生系统性抗肿瘤免疫。几个世纪以来，微生物在癌症形成、诊断、预后和治疗中的作用一直存在争议。最近的研究已经明确地声称，细菌、病毒和/或真菌在癌症中是普遍存在的，是癌症免疫治疗的关键因素，并且可被工程化以治疗转移。尽管有这些发现，但已知直接导致致癌的微生物数量仍然很少。根据现代癌症生物学对这些证据进行批判性评估并建立框架是一项重要任务。在这篇综述中，我们描述了微生物在癌症中的因果和同谋作用，并通过宿主的免疫系统追踪其影响的共同主题，本文定义为免疫肿瘤学微生物组（IOM）轴。我们进一步审查了肿瘤内微生物的证据以及操纵宿主肠道或肿瘤微生物组的方法，同时预测下一阶段的实验发现。
Historical accounts linking cancer and microbes date as early as four millennia ago. Post establishment of the germ theory of infectious diseases, clinical research of microbial influences on cancer began in 1868, when William Busch reported spontaneous tumor regressions in patients with Streptococcus pyogenes infections. Over the next century, the role of bacteria in carcinogenesis and cancer therapy was discounted due to poor reproducibility, erroneous microbiological claims, and severe toxicity in patients. However, these provided some of the first crude demonstrations of cancer immunotherapy. Contemporaneously, the viral theory of cancer began to flourish, spurred by the 1911 discovery of Rous Sarcoma Virus (RSV), which transformed benign tissue into malignant tumors in domestic fowl. The subsequent decades-long search to find a virus behind every human cancer ultimately failed, and many cancers have been fundamentally linked to somatic mutations. Now the field is encountering intriguing claims of the importance of microbes, including bacteria and fungi, in cancer and cancer therapy. This Review critically evaluates the evidence for these claims in light of modern cancer biology and immunology, and delineates the roles of microbes in cancer by examining recent advances in proposed mechanisms, diagnostics, endogenous modulation approaches, and exogenous therapeutic strategies. Few microbes directly cause cancer, but many seem complicit in its growth, often acting through the host’s immune system; conversely, several have immunostimulatory properties. Mechanistic analyses of gut microbiota-immune system interactions have demonstrated powerful effects on innate and adaptive immunity by modulating primary and secondary lymphoid tissue activities against cancer and tumor immunosurveillance. Many of these pathways invoke Toll-like receptor (TLR)-initiated cytokine signaling, but microbial metabolic effects in dietary energy harvest and short-chain fatty acid production, and antigenic mimicry with cancer cells, are also important. In preclinical models, microbial metabolites also regulate phenotypes of tumor somatic mutations and modulate immune checkpoint inhibitor efficacy. Emerging evidence also suggests the existence and functional activity of intratumoral bacteria, with overlapping immunohistochemistry, immunofluorescence, electron microscopy, and sequencing data on them in ~10 cancer types. Preliminary studies also suggest that fungi and bacteriophages contribute to gastrointestinal cancers. However, the estimated cellular abundances of intratumoral microbes is low relative to cancer cells, and knowledge of their functional repertoire and potency remains limited. Further validation of their prevalence and impact is needed in diverse cohorts and therapeutic contexts. The immunomodulatory effects of host microbiota have reinvigorated efforts to change their composition as a form of immunotherapy. Despite extensive preclinical evidence, translation of microbiota modulation approaches into humans has yet to broadly materialize into commercialized therapies. Synthetic biology approaches are also gaining traction, however, with engineered bacterial cancer therapies in preclinical and clinical trial settings. A better understanding of the roles of microbes in cancer has the opportunity to improve each stage of the cancer care cycle, but major challenges must be surmounted. Concerted efforts to characterize cancer-associated microbiota among tumor, stool, and blood samples with gold-standard contamination controls would tremendously aid this progress. This would be analogous to The Cancer Genome Atlas (TCGA)’s and International Cancer Genome Consortium (ICGC)’s roles in characterizing the cancer somatic mutation landscape. Large-scale clinical trials are currently testing the efficacy of microbiota modulation approaches, ranging from dietary modifications to intratumorally-injected, engineered bacteria. These bacterial cancer therapies, if safe and effective, could tremendously expand the cancer therapy armamentarium. Altogether, integrating the host-centric and microbial viewpoints of cancer may improve patient outcomes while providing a nuanced understanding of cancer-host-microbial evolution. Opportunities for microbes to impact cancer care. Diagnosis: Cancer-specific, blood-borne microbial DNA may complement cell-free tumor DNA (ctDNA). Prognosis: Gut and intratumoral microbiota may stratify patient outcomes; (N)R=(non)responder; TME=tumor microenvironment. Therapy: Intratumor injection of CD47 nanobody (CD47nb)-producing E. coli may create systemic antitumor immunity by enhancing dendritic cell (DC) phagocytosis, lymph node (LN) antigen (Ag) presentation, and cytotoxic T lymphocyte (CTL) activity. Microbial roles in cancer formation, diagnosis, prognosis, and treatment have been disputed for centuries. Recent studies have provocatively claimed that bacteria, viruses, and/or fungi are pervasive among cancers, key actors in cancer immunotherapy, and engineerable to treat metastases. Despite these findings, the number of microbes known to directly cause carcinogenesis remains small. Critically evaluating and building frameworks for such evidence in light of modern cancer biology is an important task. In this Review, we delineate between causal and complicit roles of microbes in cancer and trace common themes of their influence through the host’s immune system, herein defined as the immuno-oncology-microbiome (IOM) axis. We further review evidence for intratumoral microbes and approaches that manipulate the host’s gut or tumor microbiome while projecting the next phase of experimental discovery.
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影响因子：
7
作者：
Castellarin, Mauro;Warren, Rene L.;Holt, Robert A.
通讯作者：
Holt, Robert A.
影响因子：
64.8
作者：
通讯作者：
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影响因子：
7
作者：
Boot, Arnoud;Ng, Alvin W. T.;Rozen, Steven G.
通讯作者：
Rozen, Steven G.
DOI：
10.1126/science.aal5240
发表时间：
2017-12-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bullman S;Pedamallu CS;Sicinska E;Clancy TE;Zhang X;Cai D;Neuberg D;Huang K;Guevara F;Nelson T;Chipashvili O;Hagan T;Walker M;Ramachandran A;Diosdado B;Serna G;Mulet N;Landolfi S;Ramon Y Cajal S;Fasani R;Aguirre AJ;Ng K;Élez E;Ogino S;Tabernero J;Fuchs CS;Hahn WC;Nuciforo P;Meyerson M
通讯作者：
Meyerson M
影响因子：
4.6
作者：
Arthur, Janelle C.;Gharaibeh, Raad Z.;Uronis, Joshua M.;Perez-Chanona, Ernesto;Sha, Wei;Tomkovich, Sarah;Muehlbauer, Marcus;Fodor, Anthony A.;Jobin, Christian
通讯作者：
Jobin, Christian