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遗传和药理学调节 DNA 错配修复异质性肿瘤促进免疫监视。

Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance.

机构信息

Department of Oncology, University of Torino, 10060 Candiolo, TO, Italy; Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy.

Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy.

出版信息

Cancer Cell. 2023 Jan 9;41(1):196-209.e5. doi: 10.1016/j.ccell.2022.12.003. Epub 2022 Dec 29.

DOI:10.1016/j.ccell.2022.12.003
PMID:36584674
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9833846/
Abstract

Patients affected by colorectal cancer (CRC) with DNA mismatch repair deficiency (MMRd), often respond to immune checkpoint blockade therapies, while those with mismatch repair-proficient (MMRp) tumors generally do not. Interestingly, a subset of MMRp CRCs contains variable fractions of MMRd cells, but it is unknown how their presence impacts immune surveillance. We asked whether modulation of the MMRd fraction in MMR heterogeneous tumors acts as an endogenous cancer vaccine by promoting immune surveillance. To test this hypothesis, we use isogenic MMRp (Mlh1) and MMRd (Mlh1) mouse CRC cells. MMRp/MMRd cells mixed at different ratios are injected in immunocompetent mice and tumor rejection is observed when at least 50% of cells are MMRd. To enrich the MMRd fraction, MMRp/MMRd tumors are treated with 6-thioguanine, which leads to tumor rejection. These results suggest that genetic and pharmacological modulation of the DNA mismatch repair machinery potentiate the immunogenicity of MMR heterogeneous tumors.

摘要

患有 DNA 错配修复缺陷（MMRd）的结直肠癌（CRC）患者通常对免疫检查点阻断疗法有反应，而错配修复功能正常（MMRp）的肿瘤患者通常没有。有趣的是，一部分 MMRp CRC 中含有可变比例的 MMRd 细胞，但尚不清楚它们的存在如何影响免疫监视。我们想知道在 MMR 异质性肿瘤中调节 MMRd 分数是否可以通过促进免疫监视来作为一种内源性癌症疫苗。为了验证这一假设，我们使用了同源 MMRp（Mlh1）和 MMRd（Mlh1）小鼠 CRC 细胞。将不同比例混合的 MMRp/MMRd 细胞注射到免疫功能正常的小鼠中，当至少 50%的细胞为 MMRd 时，观察到肿瘤排斥。为了富集 MMRd 分数，用 6-巯基嘌呤处理 MMRp/MMRd 肿瘤，导致肿瘤排斥。这些结果表明，DNA 错配修复机制的遗传和药理学调节增强了 MMR 异质性肿瘤的免疫原性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/967b326dac17/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/d5bd1a9e875d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/ea2fb43f08cc/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/3bfe47e493ee/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/20180219731b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/bf83710f77be/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/b42102b26b1a/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/9c8734760e85/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/f29834ad36a8/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/967b326dac17/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/d5bd1a9e875d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/ea2fb43f08cc/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/3bfe47e493ee/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/20180219731b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/bf83710f77be/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/b42102b26b1a/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/9c8734760e85/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/f29834ad36a8/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a90/9833846/967b326dac17/gr8.jpg

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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients.

Cancer Discov. 2022-7-6

[2]
Temozolomide Followed by Combination With Low-Dose Ipilimumab and Nivolumab in Patients With Microsatellite-Stable, O-Methylguanine-DNA Methyltransferase-Silenced Metastatic Colorectal Cancer: The MAYA Trial.

J Clin Oncol. 2022-5-10

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Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers.

Cancers (Basel). 2021-5-27

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N Engl J Med. 2021-3-25

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Medicine (Baltimore). 2020-5

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Geographic Heterogeneity for Mismatch Repair Proteins Is Associated with Defects in DNA Repair.

Isr Med Assoc J. 2020-1

[10]
Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer.

Clin Cancer Res. 2020-3-1

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