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重塑软骨素-6-硫酸盐介导的免疫排斥增强微卫星稳定型结直肠癌对 PD-1 阻断的反应。

Remodeling Chondroitin-6-Sulfate-Mediated Immune Exclusion Enhances Anti-PD-1 Response in Colorectal Cancer with Microsatellite Stability.

机构信息

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China.

Department of Pathology, Guangzhou First People's Hospital, Guangzhou, Guangdong, P.R. China.

出版信息

Cancer Immunol Res. 2022 Feb;10(2):182-199. doi: 10.1158/2326-6066.CIR-21-0124. Epub 2021 Dec 21.

DOI:10.1158/2326-6066.CIR-21-0124
PMID:34933913
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9414301/
Abstract

Metastatic microsatellite-stable (MSS) colorectal cancer rarely responds to immune checkpoint inhibitors (ICI). Metabolism heterogeneity in the tumor microenvironment (TME) presents obstacles to antitumor immune response. Combining transcriptome (The Cancer Genome Atlas MSS colorectal cancer, = 383) and digital pathology ( = 96) analysis, we demonstrated a stroma metabolism-immune excluded subtype with poor prognosis in MSS colorectal cancer, which could be attributed to interaction between chondroitin-6-sulfate (C-6-S) metabolites and M2 macrophages, forming the "exclusion barrier" in the invasive margin. Furthermore, C-6-S derived from cancer-associated fibroblasts promoted co-nuclear translocation of pSTAT3 and GLI1, activating the JAK/STAT3 and Hedgehog pathways. experiments with C-6-S-targeted strategies decreased M2 macrophages and reprogrammed the immunosuppressive TME, leading to enhanced response to anti-PD-1 in MSS colorectal cancer. Therefore, C-6-S-induced immune exclusion represents an "immunometabolic checkpoint" that can be exploited for the application of combination strategies in MSS colorectal cancer ICI treatment.

摘要

转移性微卫星稳定（MSS）结直肠癌很少对免疫检查点抑制剂（ICI）有反应。肿瘤微环境（TME）中的代谢异质性给抗肿瘤免疫反应带来了障碍。我们结合转录组（癌症基因组图谱 MSS 结直肠癌，n = 383）和数字病理学（n = 96）分析，在 MSS 结直肠癌中证明了一种具有不良预后的基质代谢免疫排斥亚型，这可归因于软骨素-6-硫酸盐（C-6-S）代谢物与 M2 巨噬细胞之间的相互作用，在侵袭边缘形成“排斥屏障”。此外，来自癌相关成纤维细胞的 C-6-S 促进了 pSTAT3 和 GLI1 的共核易位，激活了 JAK/STAT3 和 Hedgehog 通路。用 C-6-S 靶向策略进行的实验减少了 M2 巨噬细胞，并重新编程了免疫抑制性 TME，导致对 MSS 结直肠癌中抗 PD-1 的反应增强。因此，C-6-S 诱导的免疫排斥代表了一个“免疫代谢检查点”，可用于 MSS 结直肠癌 ICI 治疗中联合策略的应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/5e45feb68445/182fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/8273875a0434/182fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/410563817501/182fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/7e57f301c407/182fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/d498bb39c408/182fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/1b1f68441f66/182fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/8ab6deeafd52/182fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/5e45feb68445/182fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/8273875a0434/182fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/410563817501/182fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/7e57f301c407/182fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/d498bb39c408/182fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/1b1f68441f66/182fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/8ab6deeafd52/182fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bef1/9414301/5e45feb68445/182fig7.jpg

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本文引用的文献

[1]
Conserved pan-cancer microenvironment subtypes predict response to immunotherapy.

Cancer Cell. 2021-6-14

[2]
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Cell Metab. 2020-11-3

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Cancer Immunol Immunother. 2019-12-31

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Cell Metab. 2020-1-7

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