Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to...

Area of Science:

• Oncology
• Immunology
• Cancer Research

Background:

• Radiotherapy (RT) effects on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) remain unclear.
• RT alone shows limited ability to prime antigen-specific T-cell responses in PDAC.
• Tumor-stromal components, like fibroblasts and collagen, can inhibit RT efficacy and interferon signaling.

Purpose of the Study:

• To investigate if RT can initiate T-cell responses in PDAC.
• To identify mechanisms hindering RT-induced anti-tumor immunity.
• To explore strategies for enhancing RT effectiveness in PDAC.

Main Methods:

• Analysis of human PDAC tissues and mouse models.
• In vitro studies using tumor-stromal components.
• Evaluation of focal adhesion kinase (FAK) inhibition.
• Preclinical studies combining RT, FAK inhibition, and checkpoint immunotherapy.
• Initiation of a clinical trial (NCT04331041) for PDAC patients.

Main Results:

• RT showed minimal T-cell priming in human and mouse PDAC models.
• Tumor stroma significantly blunted RT efficacy and interferon signaling.
• FAK inhibition restored RT efficacy, promoting T-cell priming and tumor regression in vivo.
• Combined RT, FAK inhibition, and checkpoint immunotherapy led to complete tumor regression and long-term survival in animal models.

Conclusions:

• FAK inhibition is a viable strategy to enhance RT-induced anti-tumor immunity in PDAC.
• Overcoming stromal resistance to RT is crucial for improving treatment outcomes.
• The combination of RT, FAK inhibition, and immunotherapy shows promise for PDAC treatment.