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Updated: Aug 27, 2025
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A Novel Stromal Fibroblast-Modulated 3D Tumor Spheroid Model for Studying Tumor-Stroma Interaction and Drug Discovery
Published on: February 28, 2020
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LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity
Akshay T Krishnamurty1, Justin A Shyer1, Minh Thai1
1Genentech, South San Francisco, CA, USA.
Nature
|September 28, 2022
Summary
Transforming cancer treatment: Targeting leucine-rich-repeat-containing protein 15 (LRRC15)+ cancer-associated fibroblasts (CAFs) with TGFβ inhibition may enhance anti-tumor immunity and improve immunotherapy response.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Single-cell studies reveal leucine-rich-repeat-containing protein 15 (LRRC15)+ myofibroblasts in human and mouse cancers.
- The molecular drivers and immune impact of LRRC15+ cancer-associated fibroblasts (CAFs) remain largely unknown.
Purpose of the Study:
- Investigate the in vivo development and function of LRRC15+ CAFs in pancreatic cancer.
- Determine the role of LRRC15+ CAFs in anti-tumor immunity and response to immune checkpoint blockade.
Main Methods:
- Utilized mouse models of pancreatic cancer.
- Employed genetic evidence to identify TGFβ receptor type 2 signaling as crucial for LRRC15+ myofibroblast development.
- Developed Lrrc15-diphtheria toxin receptor knock-in mice for selective CAF depletion.
Main Results:
- TGFβ receptor type 2 signaling in dermatopontin+ fibroblasts drives LRRC15+ CAF development.
- Selective depletion of LRRC15+ CAFs reduced tumor fibroblast content and shifted composition towards universal fibroblasts.
- CAF depletion enhanced CD8+ T cell effector function and augmented tumor regression with anti-PDL1 therapy.
Conclusions:
- TGFβ-dependent LRRC15+ CAFs promote tumor growth by suppressing CD8+ T cells and limiting immunotherapy efficacy.
- Targeting LRRC15+ myofibroblasts offers a potential strategy to restore homeostatic fibroblast populations and improve cancer patient outcomes and immunotherapy response.
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