Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity

Area of Science:

• Cancer Biology
• Immunology
• Genetics

Background:

• Cancer-associated fibroblasts (CAFs) are critical for tumor growth but are challenging therapeutic targets due to their functional plasticity and complex regulatory networks.
• Previous clinical trials targeting CAFs have largely failed, highlighting the need for a deeper understanding of CAF heterogeneity and regulation within the tumor microenvironment.

Purpose of the Study:

• To systematically screen patient-derived fibroblasts to identify novel regulatory circuits and potential therapeutic targets.
• To investigate the functional plasticity of CAFs and discover mechanisms that can be leveraged for anti-cancer therapies.

Main Methods:

• Development and application of a systematic screening approach using complementary CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa)-based Perturb-seq on patient-derived fibroblasts.
• Analysis of molecular checkpoints and regulatory programs, including interferon (IFN)-I response and TGF-β signaling pathways.
• Validation in murine cancer models and integration with human genomics data.

Main Results:

• Identification of an anti-tumoral interferon (IFN)-I response program that counteracts pro-tumoral TGF-β signaling in CAFs.
• Discovery of ADAM12 as a critical molecular checkpoint regulating the balance between pro-tumoral and anti-tumoral programs in fibroblasts.
• Demonstration that ablation of ADAM12 reprograms CAFs, enhances T cell-mediated immunity, and leads to tumor rejection in preclinical models.

Conclusions:

• ADAM12 plays a pivotal role in regulating CAF phenotype and function, acting as a potential therapeutic target.
• Targeting ADAM12 can reprogram cancer-associated fibroblasts to promote anti-tumor immunity and induce tumor rejection, offering a promising new therapeutic strategy.
• Findings provide a foundation for developing novel fibroblast-targeted therapies for cancer treatment.