Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE207718 | GEO | 2022/10/09
REPOSITORIES: GEO
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Project description:The effect of radiation therapy (RT) on tumor immunity in PDAC is not well understood. To better understand if RT can prime antigen-specific T cell responses, we analyzed human PDAC tissues and PDAC GEMMs. In both settings, we found little to support evidence of RT-induced T cell priming. Using in-vitro systems, we found tumor stromal components, including fibroblasts and collagen, synergize to both blunt RT efficacy and impair RT-induced interferon signaling. Focal Adhesion Kinase (FAK) inhibition rescued RT efficacy in-vitro and in-vivo, leading to tumor regression, T cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of VS-6063 in combination with SBRT in PDAC patients (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in GEMMs. Finally, the addition of checkpoint immunotherapy to RT and FAKi in animal models led to complete tumor regression and long-term survival.
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Project description:The effect of radiation therapy (RT) on tumor immunity in PDAC is not well understood. To better understand if RT can prime antigen-specific T cell responses, we analyzed human PDAC tissues and PDAC GEMMs. In both settings, we found little to support evidence of RT-induced T cell priming. Using in-vitro systems, we found tumor stromal components, including fibroblasts and collagen, synergize to both blunt RT efficacy and impair RT-induced interferon signaling. Focal Adhesion Kinase (FAK) inhibition rescued RT efficacy in-vitro and in-vivo, leading to tumor regression, T cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of VS-6063 in combination with SBRT in PDAC patients (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in GEMMs. Finally, the addition of checkpoint immunotherapy to RT and FAKi in animal models led to complete tumor regression and long-term survival.
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Project description:The effect of radiation therapy (RT) on tumor immunity in PDAC is not well understood. To better understand if RT can prime antigen-specific T cell responses, we analyzed human PDAC tissues and PDAC GEMMs. In both settings, we found little to support evidence of RT-induced T cell priming. Using in-vitro systems, we found tumor stromal components, including fibroblasts and collagen, synergize to both blunt RT efficacy and impair RT-induced interferon signaling. Focal Adhesion Kinase (FAK) inhibition rescued RT efficacy in-vitro and in-vivo, leading to tumor regression, T cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of VS-6063 in combination with SBRT in PDAC patients (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in GEMMs. Finally, the addition of checkpoint immunotherapy to RT and FAKi in animal models led to complete tumor regression and long-term survival.
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