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AACR 官方博客《Cancer Research Catalyst》发文：基于菌群预测免疫疗法应答

10月15日

来源：癌症研究UPDATE

以下内容原文发布于AACR官方博客《Cancer Research Catalyst》, 中文内容仅做参考，请点击文末“阅读原文”，阅览原文内容。

最近的一项研究表明，患者胃肠道中的细菌（即肠道菌群）可以帮助临床医生就免疫检查点抑制剂（ICI）做出更明智的决定。作为一种免疫疗法，ICI可以增强免疫系统发现和攻击癌症的天然能力。

考虑到ICI的副作用和高昂费用，研究人员正在尝试各种方法以找出最有可能从该疗法获益的患者，从而让可能疗效不佳的大多数患者免受此类治疗的毒性和经济负担等影响。目前，高突变负荷、错配修复缺陷和免疫检查点蛋白PD-L1表达情况等肿瘤生物标志物已被用于确定ICI的治疗资格。然而，由于表达量低或表达量可变等原因，这些生物标志物用于预测应答时并不完全可靠，或存在较大的检测难度，因此研究人员一直在寻找更好的方法。

尚处于探索阶段的一种设想是检测肠道菌群，根据已有报道，肠道菌群对免疫系统有着深远的影响。法国古斯塔夫-鲁西癌症中心的Laurence Zitvogel博士（MD、PhD）和Guido Kroemer博士（MD、PhD）近日在美国癌症研究协会（AACR）旗下期刊 Cancer Discovery 上发表了一篇综述，详细阐述了患者肠道菌群的变化（抗生素使用等原因导致）如何影响抗癌相关的免疫活动。

他们解释称，肠道细菌的变化会抑制抗肿瘤免疫应答，降低免疫疗法的疗效，而可能的原因则包括：消耗了保证免疫功能所需的营养物质，激活免疫信号传导的微生物模式减少了，以及失去了可以感染癌细胞并在肿瘤内引发免疫应答的细菌，以及其它机制等。

了解更多内容，请阅读以下原文。

A ‘Gutsy’ Approach to Predict Immunotherapy Responses

A recent study suggests that the bacteria in a patient’s gastrointestinal tract—i.e., the gut microbiome—could help clinicians make more informed decisions about immune checkpoint inhibitors (ICIs), a type of immunotherapy that boosts the immune system’s natural ability to find and attack cancers.

Given the side effects and steep costs associated with ICIs, researchers are looking for ways to figure out who is most likely to benefit so that the majority of patients whose tumors are unlikely to respond can be spared the toxicities and financial burdens of these treatments. Currently, tumor biomarkers such as high mutation burden, deficiency in mismatch repair, and expression of the immune checkpoint protein PD-L1 are used to determine eligibility for ICIs. These biomarkers, however, can be unreliable at predicting response and difficult to detect due to low or variable expression, leaving researchers in search of better methods.

One idea under exploration is to examine the gut microbiome, which has been reported to have a profound influence on the immune system. In a recent commentary published in the American Association for Cancer Research (AACR) journal Cancer Discovery , Laurence Zitvogel, MD, PhD, and Guido Kroemer, MD, PhD, from Gustave Roussy Cancer Center in France, detailed how changes to a patient’s gut microbiome—such as those caused by antibiotic use—can affect immune activity against cancer.

They explained that changes to gut bacteria can suppress the antitumor immune response and reduce the efficacy of immunotherapy due to the depletion of nutrients required for adequate immune function, fewer microbial patterns that activate immune signaling, and the loss of bacteria that can infect cancer cells and trigger an immune response within the tumor, among other mechanisms.

How Can the Gut Microbiome Guide Immunotherapy Use?

Building on this research, Zitvogel, Kroemer, and colleagues explored whether changes to a patient’s gut bacteria could provide clues about their chances of responding to immunotherapy. Earlier studies had often come to contradicting conclusions about which bacteria impacted ICI efficacy, so the researchers opted not to focus on any particular bacterial species in isolation and instead investigated the communities that gut bacteria form with one another.

As reported in Cell , they began by sequencing fecal samples from patients with advanced lung cancer to define the bacterial species present in each patient’s gut before and during ICI treatment. By comparing the bacterial communities present in patients who did and did not experience responses to ICI treatment, they defined which bacterial communities were associated with treatment response and which were associated with treatment resistance.

The researchers categorized these communities into two “species-interacting groups” (SIGs)—SIG1, comprised of bacterial communities associated with ICI resistance, and SIG2, of communities associated with ICI response. The ratio of SIG1 to SIG2, combined with the relative abundance of the bacterium Akkermansia muciniphila , was used to calculate a topological score (termed TOPOSCORE by the authors) that estimated a patient’s likelihood of ICI response with greater accuracy than the established predictive biomarker PD-L1.

Since the type of complex genetic sequencing used to calculate TOPOSCORE is time-consuming, expensive, and not widely available, the researchers translated their method into a simplified PCR test that could be more easily implemented in the clinic. The simplified test, designed to detect 21 bacterial species instead of 83, showed comparable performance to the more complicated method across diverse cancer types.

The authors propose TOPOSCORE (in either the full or simplified form) as a clinical tool to determine patient eligibility for ICIs. Further, they speculate that TOPOSCORE could even identify patients whose chances of treatment response might benefit from interventions that modify their gut microbiomes—prebiotics or fecal transplants, for example.

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10月15日

赵建国

南京市高淳人民医院 | 肿瘤内科

基于菌群预测免疫疗法应答