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EDIL3 as an Angiogenic Target of Immune Exclusion Following Checkpoint Blockade
Saba Tabasum1,2,3, Dinesh Thapa1,2,3, Anita Giobbie-Hurder3,4
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
Cancer Immunology Research
|September 20, 2023
Summary
A novel antibody response against EGF-like repeats and discoidin I-like domains protein 3 (EDIL3) was found in patients responding to cancer immunotherapy. High EDIL3 levels correlate with poor prognosis and immune exclusion, suggesting it as a therapeutic target.
Area of Science:
- Immunology and Cancer Biology
- Tumor Microenvironment and Angiogenesis
Background:
- Immune checkpoint blockade (ICB) is a standard cancer therapy, but its efficacy can be improved by combination strategies.
- Combining antiangiogenic agents with ICB shows promise, yet the underlying mechanisms require further elucidation.
- EGF-like repeats and discoidin I-like domains protein 3 (EDIL3) has been linked to poor prognosis in various cancers.
Purpose of the Study:
- To investigate the mechanistic basis for synergy between antiangiogenic agents and ICB in cancer treatment.
- To identify novel biomarkers and therapeutic targets associated with favorable responses to combined immunotherapies.
Main Methods:
- Screening of patient sera for antibody responses against extracellular proteins in responders to ipilimumab and bevacizumab.
- Bioinformatic analyses including Tumor Immune Dysfunction and Exclusion (TIDE), TCGA-SKCM, and CheckMate 064 data.
- In vitro studies using patient-derived cancer-associated fibroblasts (CAFs) and tumor endothelial cells (TECs) with 3D microfluidic and 2D transmigration assays.
Main Results:
- A high-titer antibody response against EDIL3 was discovered in patients with favorable outcomes from ICB and antiangiogenic therapy.
- Elevated EDIL3 levels were associated with immune exclusion signatures, increased TGFβ signaling in fibroblasts, angiogenesis, and epithelial-to-mesenchymal transition.
- EDIL3 was shown to enhance angiogenesis and disrupt T-cell migration by interfering with LFA-1/ICAM-1 interactions, contributing to immune exclusion.
Conclusions:
- EDIL3 plays a significant role in promoting an immunosuppressive tumor microenvironment and hindering ICB efficacy.
- Targeting EDIL3 may overcome immune exclusion and improve the effectiveness of immune checkpoint blockade therapy.
- Circulating EDIL3 levels could serve as a predictive biomarker for response to combined immunotherapies.
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