AbstractApproximately 15% of locally advanced colorectal cancers (CRC) have DNA mismatch repair deficiency (dMMR), resulting in high microsatellite instability and a high tumour mutational burden. These cancers are frequently sensitive to therapy with immune-checkpoint inhibitors (ICIs) in the metastatic setting.

摘要大约15%的局部晚期结直肠癌（CRC）患有DNA错配修复缺陷（dMMR），导致高微卫星不稳定性和高肿瘤突变负担。这些癌症通常对转移环境中的免疫检查点抑制剂（ICI）治疗敏感。

This sensitivity seems to be even more pronounced in locally advanced disease, and organ preservation has become a realistic aim in ongoing clinical trials involving patients with dMMR rectal cancer. By contrast, metastatic CRCs with proficient DNA mismatch repair (pMMR) are generally resistant to ICIs, although a proportion of locally advanced pMMR tumours seem to have a high degree of sensitivity to ICIs.

这种敏感性在局部晚期疾病中似乎更为明显，器官保存已成为正在进行的涉及dMMR直肠癌患者的临床试验的现实目标。相比之下，具有熟练DNA错配修复（pMMR）的转移性CRC通常对ICI具有抗性，尽管一部分局部晚期pMMR肿瘤似乎对ICI具有高度敏感性。

In this Review, we describe the current and emerging clinical evidence supporting the use of neoadjuvant ICIs in patients with dMMR and pMMR CRC, and the potential advantages (based on a biological rationale) of such an approach. We discuss how neoadjuvant ‘window-of-opportunity’ trials are being leveraged to progress biomarker discovery and we provide an overview of potential predictive biomarkers of response to ICIs, exploring the challenges faced when evaluating such biomarkers in biopsy-derived samples.

在这篇综述中，我们描述了支持在dMMR和pMMR CRC患者中使用新辅助ICI的当前和新兴临床证据，以及这种方法的潜在优势（基于生物学原理）。我们讨论了如何利用新辅助“机会之窗”试验来推进生物标志物的发现，并概述了对ICI反应的潜在预测性生物标志物，探讨了在活检衍生样品中评估此类生物标志物时面临的挑战。

Lastly, we describe how these discoveries might be used to drive a rational approach to trialling novel immunotherapeutic strategies in patients with pMMR CRC, with the ultimate aim of disease eradication and the generation of long-term immunosurveillance.Key points.

最后，我们描述了如何利用这些发现来推动合理的方法，在pMMR CRC患者中试验新的免疫治疗策略，最终目的是根除疾病和产生长期免疫监视。关键点。

Colorectal cancers (CRCs) with DNA mismatch repair deficiency and/or high microsatellite instability (dMMR/MSI-H) have high response rates to immune-checkpoint inhibitors (ICIs) in the metastatic setting.

具有DNA错配修复缺陷和/或高微卫星不稳定性（dMMR/MSI-H）的结直肠癌（CRC）在转移环境中对免疫检查点抑制剂（ICI）具有高反应率。

Locally advanced dMMR/MSI-H CRCs have dramatic responses to ICIs in phase II trials, with validation trials ongoing. As a result, organ preservation is a realistic aim in current trials involving patients with rectal cancer whereas additional challenges are faced in colon cancer.

。因此，在目前涉及直肠癌患者的试验中，器官保存是一个现实的目标，而结肠癌面临着额外的挑战。

In comparison with patients with dMMR/MSI-H CRC, those with proficient DNA mismatch repair and/or microsatellite stable (pMMR/MSS) disease tend to have inferior responses to ICIs, although impressive responses have been observed in a subset of patients in the neoadjuvant setting.

与dMMR/MSI-H CRC患者相比，那些具有熟练DNA错配修复和/或微卫星稳定（pMMR/MSS）疾病的患者对ICI的反应往往较差，尽管在新辅助治疗的一部分患者中观察到了令人印象深刻的反应。

pMMR/MSS CRCs are biologically heterogeneous and thus novel predictive biomarkers are required to determine which patients can derive the most benefit from currently used ICIs.

pMMR/MSS CRC在生物学上是异质的，因此需要新的预测性生物标志物来确定哪些患者可以从当前使用的ICI中获得最大的益处。

Neoadjuvant ‘window-of-opportunity’ trials aim to enhance the pace of immunotherapeutic drug development and facilitate assessment of both tumours that do and do not respond to treatment, aiding novel biomarker discovery.

新辅助“机会之窗”试验旨在提高免疫治疗药物开发的速度，并促进对治疗有反应和无反应的两种肿瘤的评估，从而有助于发现新的生物标志物。

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Fig. 1: Biomarker discovery and clinical trials.Fig. 2: Biomarker discovery and validation.

图1：生物标志物发现和临床试验。图2：生物标志物的发现和验证。

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Download referencesAcknowledgementsC.J.M.W. receives funding from Cancer Research UK (RCCCTF-Nov21/100001). A.M.P. receives funding from Fonds Wetenschappelijk Onderzoek (1SF0424N).Author informationAuthor notesThese authors contributed equally: Christopher J. M. Williams, Allyson M.

下载referencesAcknowledgementsC。J、 M.W.获得英国癌症研究所（RCCCTF-Nov21/100001）的资助。A、 M.P.从Fonds Wetenschapelijk Onderzoek（1SF0424N）获得资金。作者信息作者注意到这些作者做出了同样的贡献：克里斯托弗·J·M·威廉姆斯，Allyson M。

Peddle.These authors jointly supervised this work: Gary M. Middleton, Sabine Tejpar.Authors and AffiliationsDivision of Oncology, Leeds Institute of Medical Research, University of Leeds, Leeds, UKChristopher J. M. Williams & Jenny F. SeligmannDepartment of Oncology, KU Leuven, Leuven, BelgiumAllyson M.

兜售。这些作者共同监督了这项工作：Gary M.Middleton，Sabine Tejpar。作者和附属机构英国利兹大学利兹医学研究所利兹医学研究所肿瘤学系Christopher J.M.Williams＆Jenny F.Seligmann肿瘤科，鲁汶大学鲁汶分校，BelgiumAllyson M。

Peddle & Sabine TejparDepartment of Gastrointestinal Oncology, City of Hope Orange County Lennar Foundation Cancer Center, Irvine, CA, USAPashtoon M. KasiSchool of Cancer Sciences, University of Glasgow, Glasgow, UKCampbell S. RoxburghInstitute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UKGary M.

Peddle＆Sabine Tejparde希望之城奥兰治县伦纳基金会癌症中心胃肠道肿瘤学系，加利福尼亚州欧文市，USAPSHTOON M.KasiSchool of Cancer Sciences，格拉斯哥大学，格拉斯哥，UKCampbell S.RoxburghInstitute of Immunology and Immunotherapy，伯明翰大学，伯明翰，UKGary M。

MiddletonAuthorsChristopher J. M. WilliamsView author publicationsYou can also search for this author in.

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PubMed Google ScholarContributionsC.J.M.W. and A.M.P. wrote the manuscript. All authors researched data, substantially contributed to discussions of content, and reviewed and edited the manuscript before submission.Corresponding authorsCorrespondence to

PubMed谷歌学术贡献中心。J、 M.W.和A.M.P.写了手稿。所有作者都研究了数据，对内容的讨论做出了重大贡献，并在提交前对稿件进行了审查和编辑。通讯作者通讯

Christopher J. M. Williams or Allyson M. Peddle.Ethics declarations

克里斯托弗·J·M·威廉姆斯（ChristopherJ.M.Williams）或阿利森·M·佩德尔（AllysonM.Peddle）。道德宣言

Competing interests

相互竞争的利益

C.J.M.W. has received institutional research funding from GSK, Merck Serono, and Roche Diagnostics and honoraria from Merck Serono, Roche Diagnostics, Servier and Tactics MD. A.M.P. has received institutional research funding from GSK. P.M.K. has received institutional research funding from Agenus. J.F.S.

C、 J.M.W.获得了GSK、Merck Serono和Roche Diagnostics的机构研究资金，以及Merck Serono、Roche Diagnostics、Servier和Tactics MD的酬金。A.M.P.获得了GSK的机构研究资金。P、 M.K.已获得Agenus的机构研究资助。J、 F.S。

has received institutional research funding from Amgen, GSK, Merck Serono, and Pierre Fabre Medicament and honoraria from AstraZeneca, Biocartis, BMS, GSK, Jazz Pharmaceuticals, Merck Serono, Pierre Fabre Medicament, Roche Diagnostics, Sanofi, Seagen, Servier and Takeda. C.S.R. has received institutional research funding from GSK.

已获得安进（Amgen）、葛兰素史克（GSK）、默克塞隆（Merck Serono）和皮埃尔·法伯（Pierre Fabre）药物的机构研究资助，以及阿斯利康（AstraZeneca）、生物艺术（Biocartis）、BMS、葛兰素史克（GSK）、爵士制药（Jazz Pharmaceuticals）、默克塞隆（Merck Serono）、皮埃尔·法伯（Pierre Fabre）药物、罗氏。C、 S.R.已获得GSK的机构研究资助。

G.M.M. has received institutional research funding from AstraZeneca. S.T. has received institutional research funding from GSK..

G、 M.M.已获得阿斯利康的机构研究资助。S、 T.已获得GSK的机构研究资助。。

Peer review

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Peer review information

同行评审信息

Nature Reviews Clinical Oncology thanks S. Lonardi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

《自然评论》临床肿瘤学感谢S.Lonardi和另一位匿名审稿人对这项工作的同行评审做出的贡献。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary InformationRights and permissionsSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.Reprints and permissionsAbout this articleCite this articleWilliams, C.J.M., Peddle, A.M., Kasi, P.M.

Additional informationPublisher的注释Springer Nature在已发布地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充信息权利和许可Pringer Nature或其许可方（例如协会或其他合作伙伴）根据与作者或其他权利持有人的出版协议对本文拥有独家权利；本文接受稿件版本的作者自行存档仅受此类出版协议和适用法律的条款管辖。转载和许可本文引用本文Williams，C.J.M.，Peddle，A.M.，Kasi，P.M。

et al. Neoadjuvant immunotherapy for dMMR and pMMR colorectal cancers: therapeutic strategies and putative biomarkers of response..

等。dMMR和pMMR结直肠癌的新辅助免疫治疗：治疗策略和推定的反应生物标志物。。

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