2023 World Conference on Lung Cancer (Posters)-P1.09. SFRP2+ CAFs Hinder Abscopal Effect from Combined Radiotherapy and Immunotherapy by Forming a Hostile Perivascular Niche

P1.09. SFRP2+ CAFs Hinder Abscopal Effect from Combined Radiotherapy and Immunotherapy by Forming a Hostile Perivascular Niche - PDF(Abstract)

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This study aimed to investigate why the abscopal effect, a phenomenon where radiation therapy causes regression of tumors outside the radiation field, is not consistently achieved when combined with immunotherapy. The researchers used a mouse model of lung cancer that had shown primary resistance to immune checkpoint inhibitors (ICIs). They found that the combination of radiotherapy and ICI reduced tumor burden at the irradiated site, but had no effect on abscopal tumors. RNA sequencing data revealed that the abscopal tumors had enrichment of extracellular structure organization pathways, with SFRP2 identified as a central hub. SFRP2 was found to be expressed in cancer-associated fibroblasts (CAFs) and its expression increased in abscopal tumors after combined therapy.<br /><br />Further experiments showed that blocking SFRP2, followed by combined radiotherapy and ICI, led to regression of abscopal tumors by increasing the infiltration and cytotoxicity of CD8 T cells. The researchers demonstrated that SFRP2 CAFs induced apoptosis of CD8 T cells, creating an immunosuppressive perivascular niche. The spatial transcriptome analysis confirmed that SFRP2 CAFs were located near blood vessels and surrounded by macrophages, creating an unfavorable immune environment. Lineage tracing assays revealed that SFRP2 CAFs were derived from pericytes.<br /><br />The researchers also discovered that irradiated tumors released IGF-1, which facilitated the transition of pericytes into fibroblasts and stimulated SFRP2 expression. The findings suggest that SFRP2 CAFs hinder the abscopal effect by inducing CD8 T cell apoptosis and creating an immunosuppressive perivascular niche in lung cancer. Targeting SFRP2 CAFs might help recondition the tumor microenvironment and promote the abscopal effect. This study provides important insights into the mechanisms behind the limited success of combining radiotherapy and immunotherapy in achieving an abscopal effect.

Asset Subtitle

Zhang Yanpei

Meta Tag

Speaker Zhang Yanpei

Topic Tumor Biology: Translational Biology - IO

Keywords

abscopal effect

radiation therapy

immunotherapy

mouse model

lung cancer

immune checkpoint inhibitors

RNA sequencing

SFRP2

cancer-associated fibroblasts

CD8 T cells