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TSG-6+ 肿瘤相关成纤维细胞调节髓样细胞反应，并削弱胰腺癌对免疫检查点治疗的抗肿瘤反应。

TSG-6+ cancer-associated fibroblasts modulate myeloid cell responses and impair anti-tumor response to immune checkpoint therapy in pancreatic cancer.

机构信息

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

出版信息

Nat Commun. 2024 Jul 10;15(1):5291. doi: 10.1038/s41467-024-49189-x.

DOI:10.1038/s41467-024-49189-x
PMID:38987547
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11237123/
Abstract

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. TSG-6 inhibition in combination with ICT improves therapy response and survival in pancreatic tumor-bearing mice by reducing macrophages expressing immunosuppressive phenotypes and increasing CD8 T cells. Overall, our findings propose TSG-6 as a therapeutic target to enhance ICT response in non-responsive tumors.

摘要

免疫检查点治疗（ICT）耐药性是一个日益严峻的临床挑战。肿瘤微环境（TME）及其组成部分，即肿瘤相关巨噬细胞（TAMs）和癌症相关成纤维细胞（CAFs），在 ICT 耐药性中起着关键作用；然而，其潜在机制仍在研究中。在这项研究中，我们发现与 ICT 敏感的黑色素瘤肿瘤相比，TNF 刺激因子 6（TSG-6）在 ICT 耐药性胰腺肿瘤中的表达水平更高，无论是在小鼠还是人类中都是如此。TSG-6 由 TME 中的 CAFs 表达，在 TME 中，抑制性巨噬细胞表达 Arg1、Mafb 和 Mrc1，同时表达 TSG-6 配体 Cd44，占主导地位。此外，表达 TSG-6 的 CAFs 与 TME 中表达 CD44 的巨噬细胞共定位。在胰腺肿瘤荷瘤小鼠中，联合 ICT 抑制 TSG-6 可减少表达免疫抑制表型的巨噬细胞并增加 CD8 T 细胞，从而提高治疗反应和生存率。总的来说，我们的研究结果表明 TSG-6 可作为一种治疗靶点，增强对无反应性肿瘤的 ICT 反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/7c1270fa2069/41467_2024_49189_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/b327525b9b2e/41467_2024_49189_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/a67cc3eb6fbd/41467_2024_49189_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/1823da3e6af3/41467_2024_49189_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/152c31603acd/41467_2024_49189_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/ed9f75a5b5c9/41467_2024_49189_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/7c1270fa2069/41467_2024_49189_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/b327525b9b2e/41467_2024_49189_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/a67cc3eb6fbd/41467_2024_49189_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/1823da3e6af3/41467_2024_49189_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/152c31603acd/41467_2024_49189_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/ed9f75a5b5c9/41467_2024_49189_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65cd/11237123/7c1270fa2069/41467_2024_49189_Fig6_HTML.jpg

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引用本文的文献

[1]
Cancer-associated fibroblasts as mediators of tissue microenvironment remodeling in cancer.

Curr Opin Cell Biol. 2025-7-14

[2]
Emerging frontiers in adoptive cell therapies: innovations, challenges, and future perspectives.

Med Oncol. 2025-6-15

[3]
Tumor-associated macrophages remodel the suppressive tumor immune microenvironment and targeted therapy for immunotherapy.

J Exp Clin Cancer Res. 2025-5-16

[4]
Upregulation of long noncoding RNAs and is associated with intrahepatic cholangiocarcinoma.

Sci Prog. 2025

[5]
Lymphocyte antigen 6 family member E suppresses apoptosis and promotes pancreatic cancer growth and migration via Wnt/β-catenin pathway activation.

Sci Rep. 2024-8-30

本文引用的文献

[1]
Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment.

Nat Commun. 2022-11-4

[2]
Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.

Cancer Cell. 2022-11-14

[3]
LRRC15 myofibroblasts dictate the stromal setpoint to suppress tumour immunity.

Nature. 2022-11

[4]
Macrophages as tools and targets in cancer therapy.

Nat Rev Drug Discov. 2022-11

[5]
Myeloid cell-targeted therapies for solid tumours.

Nat Rev Immunol. 2023-2

[6]
TSG-6 promotes Cancer Cell aggressiveness in a CD44-Dependent Manner and Reprograms Normal Fibroblasts to create a Pro-metastatic Microenvironment in Colorectal Cancer.

Int J Biol Sci. 2022

[7]
Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma.

J Clin Oncol. 2022-1-10

[8]
High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege.

J Immunother Cancer. 2021-8

[9]
Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.

Nature. 2021-7

[10]
Reduced hyaluronan cross-linking induces breast cancer malignancy in a CAF-dependent manner.

Cell Death Dis. 2021-6-7

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