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Immunosuppressive MFAP2+ cancer associated fibroblasts conferred unfavorable prognosis and therapeutic resistance in gastric cancer

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Abstract

Purpose

To explore the predictive merit of MFAP2+ cancer associated fibroblasts (CAFs) infiltration for clinical outcomes and adjuvant chemotherapy or immunotherapy responsiveness in gastric cancer (GC).

Methods

In this study, several independent cohorts were included respectively to dissect the relationship of clinical outcomes, therapeutic responses and tumor microenvironment with different MFAP2+ CAFs infiltration. Drug sensitivity analysis was conducted to predict the relationship between MFAP2+ CAFs infiltration and targeted drug response. Kaplan–Meier curves and the log-rank test were used to compare clinical outcomes of patients with different MFAP2+ CAFs infiltration.

Results

High MFAP2+ CAFs infiltration yielded inferior prognosis in terms of overall survival, progress free survival and recurrence free survival in GC. Patients with low MFAP2+ CAFs infiltration were more likely to gain benefit from adjuvant therapy. Moreover, low MFAP2+ CAFs infiltration could predict a promising response to immunotherapy in GC patients. MFAP2+ CAFs with immunosuppressive features were highly relevant to immune evasive contexture characterized by the dysfunction of CD8+ T cells. We found that MFAP2+ CAFs communicated with T cells, B cells and Macrophages through releasing macrophage migration inhibitor factor (MIF), which further suggested that MFAP2+ CAFs might promote therapeutic resistance through regulating T cells dysfunction and M2 macrophages polarization.

Conclusion

Immunosuppressive MFAP2+ CAFs constructed an immune evasive tumor microenvironment characterized by incapacitated immune effector cells, consequently predicting inferior clinical outcomes and response on adjuvant therapy and immunotherapy in patients with GC. The potential of immunosuppressive MFAP2+ CAFs as a therapeutic target for GC deserved thoroughly exploration.

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Data availability

Publicly available datasets were analyzed in this study. These data could be found here: UCSC XENA (https://xenabrowser.net/datapages/), GEO (https://www.ncbi.nlm.nih.gov/geo/), Tumor Immune Dysfunction and Exclusion database (http://tide.dfci.harvard.edu) and The Genomics of Drug Sensitivity in Cancer database (https://www.cancerrxgene.org/). Other raw data supporting the conclusions of this article will be available from the corresponding author upon reasonable request.

Abbreviations

MFAP2 :

Microfibril Associated Protein 2

GC :

Gastric cancer

CAFs :

Cancer associated fibroblasts

ICB :

Immune checkpoint blockade

myCAFs :

Myofibroblastic cancer associated fibroblasts

iCAFs :

Inflammatory cancer associated fibroblasts

TCGA :

The Cancer Genome Atlas

FPKM :

Fragments per kilobase million

TPM :

Transcripts per kilobase millions

ACRG :

Asian Cancer Research Group

SMC :

Samsung Medical Center

TIDE :

Tumor Immune Dysfunction and Exclusion

SD :

Stable disease

PD :

Progressive disease

PR :

Partial response

CR :

Complete response

ScRNA-seq :

Single-cell RNA sequencing

GDSC :

Genomics of Drug Sensitivity in Cancer

IC50 :

Half-maximal inhibitory concentration

ROC :

Receiver operating characteristic

AUC :

The area under the curve

MSI :

Microsatellite instability

GS :

Genome stable

EBV :

Epstein-Barr virus

CIN :

Chromosomal instability

EMT :

Epithelial mesenchymal transformation

Pan-F TBRS :

Panfibroblast TGFβ response characteristics

OS :

Overall survival

RFS :

Recurrence free survival

PFS :

Progress free survival

GEO :

Gene Expression Omnibus

GSEA :

Gene set enrichment analysis

MIF :

Macrophage migration inhibitor factor

TRG :

Tumor regression grade

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Funding

This study was sponsored by Natural Science Foundation of Shanghai (21ZR1414600), Shanghai Pujiang Program (2019PJD007), Shanghai Sailing Program (20YF1409200) and National Natural Science Foundation of China (82002545). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript.

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  1. Rongyuan Wei and Junquan Song contributed equally to this work.

Authors and Affiliations

  1. Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Rongyuan Wei, Junquan Song, Xuanjun Liu, Shiying Huo, Chenchen Liu & Xiaowen Liu

  2. Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China

    Rongyuan Wei, Junquan Song, Xuanjun Liu, Shiying Huo, Chenchen Liu & Xiaowen Liu

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  1. Rongyuan Wei
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Contributions

LXW and LCC conceived and designed this study. WRY, SJQ, LXJ, HSY analyzed the data and drafted the manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Chenchen Liu or Xiaowen Liu.

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Supplementary Information

ESM 1 Supplementary Figure 1 identification of relationship between MFAP2 and CAFs and prognostic merit of CAFs and MFAP2+ CAFs in GC. (A) The correlation of MFAP2 and CAFs via TIDE, XCELL, EPIC algorithms. (B) Kaplan–Meier curves of OS and RFS of low MFAP2+ CAFs and high MFAP2+ CAFs group stratified in GSE26942 cohort. (C) Kaplan–Meier curves of OS and PFS of low CAFs and high CAFs group stratified in TCGA cohort. (D) Kaplan–Meier curves of OS and PFS of low CAFs and high CAFs group stratified in ACRG cohort.

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ESM 2 Supplementary Figure 2 Prognostic merit of type I collagen and regulatory factors of MFAP2+ CAFs in the tumor microenvironment. (A) Kaplan–Meier curves of OS and PFS of low type I collagen content group and high type I collagen content group stratified in TCGA cohort. (B) Different regulatory factors of MFAP2+ CAFs and MFAP2- CAFs in the tumor microenvironment (*P<0.05; **P<0.01; ***P<0.001, Wilcoxon test).

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Wei, R., Song, J., Liu, X. et al. Immunosuppressive MFAP2+ cancer associated fibroblasts conferred unfavorable prognosis and therapeutic resistance in gastric cancer. Cell Oncol. 47, 55–68 (2024). https://doi.org/10.1007/s13402-023-00849-y

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  • DOI: https://doi.org/10.1007/s13402-023-00849-y

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