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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [scRNA seq data from mice]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE207111 | GEO | 2022/10/09

REPOSITORIES: GEO

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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [in vitro]

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.

2022-10-09 | GSE207717 | GEO

Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [exp2]

2022-10-09 | GSE207536 | GEO

Modulation of the human pancreatic ductal adenocarcinoma immune microenvironment by stereotactic body radiotherapy

Project description:Purpose: Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC) that can effectively prime cytotoxic T cells by inducing immunogenic tumor cell death in preclinical models. SBRT effects on human PDAC have yet to be thoroughly investigated, therefore, this study aimed to characterize immunomodulation in the human PDAC tumor microenvironment following therapy. Experimental Design: Tumor samples were obtained from patients with resectable PDAC. Radiotherapy was delivered a median of seven days prior to surgical resection, and sections were analyzed by multiplex IHC (mIHC), RNA-Seq, and T cell receptor sequencing (TCR-Seq). Results: Analysis of SBRT-treated tumor tissue indicated reduced tumor cell density and increased immunogenic cell death relative to untreated controls. Radiotherapy promoted collagen deposition, however, vasculature was unaffected and spatial analyses lacked evidence of T cell sequestration. Conversely, SBRT resulted in fewer tertiary lymphoid structures and failed to lessen or reprogram abundant immune suppressor populations. Higher percentages of PD-1+ T cells were observed following SBRT, and a subset of tumors displayed more clonal T cell repertoires. Conclusions: These findings suggest that SBRT augmentation of antitumor immunogenicity may be dampened by an overabundance of refractory immunosuppressive populations, and support the continued development of SBRT/immunotherapy combination for human PDAC.

2021-10-08 | GSE185311 | GEO

Stromal evolution of cancer-associated fibroblasts in PDAC GEMMs

Project description:Stromal evolution of cancer-associated fibroblasts in PDAC GEMMs

| PRJEB35138 | ENA

Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors

Project description:Paracrine activation of pro-fibrotic sonic hedgehog (sHH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of sHH-mediated tumor-stroma crosstalk with smoothened inhibitors transiently increases tumor permeability and macromolecule delivery. Using diffusion-weighted magnetic resonance (DW-MR) imaging, we demonstrate in multiple patient-derived xenografts (PDX) that responders to short-term sHH inhibitor exposure show increased permeability with proportionate increases in tumor diffusivity. However, a subset of PDXs fails to respond. Responders show co-induction of epithelial-mesenchymal transition (EMT), elevated FGF drive, and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1). A pan-FGFR inhibitor (NVP-BGJ398) reverses EMT and nuclear FGFR1 accumulation without compromising the tumor priming effect. This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical requirement for patient stratification

2023-12-12 | GSE159334 | GEO

Characterization of Genomic Heterogeneity and Evolution in Pancreatic Ductal Adenocarcinoma of KPC and KPTC

Project description:Identification of somatic sequence and structural alterations and their intra-tumor heterogeneity in PDAC tumors from GEMMs

2019-12-03 | GSE132235 | GEO

Combined PI3K/mTOR and MEK Inhibition Provides Broad Anti-Tumor Activity in Faithful Murine Cancer Models

Project description:Anticancer drug development is an inefficient process, with potential therapeutics demonstrating a high attrition rate due to lack of efficacy in Phase II/III testing. In an effort to develop improved pre-clinical predictors of efficacy, we and others have turned to testing in genetically engineered murine models (GEMMs) of cancer, which may offer some advantages to in vitro and xenograft systems. Specifically, we assessed the activity of 16 treatment regimens in a Ras-driven, Ink4a/Arf-deficient melanoma GEMM. Like human RAS-mutant melanoma, this GEMM was refractory to standard chemotherapy and single-agent small molecule therapies. Only one regimen exhibited significant anti-tumor activity in this model: combined treatment with AZD6244 (MEK inhibitor) and BEZ235 (dual PI3K/mTOR inhibitor), which produced marked tumor regression and improved survival. Given the surprising activity of the “AZD/BEZ” combination in a melanoma GEMM, we next tested this regimen in a Ras-driven orthotopic-transplant model of “claudin-low” breast cancer, which shares some gene expression features with melanoma. The AZD/BEZ regimen also exhibited significant activity in this related Ras-driven model, leading us to testing in even more diverse GEMMs of basal-like and luminal breast cancer. The AZD/BEZ combination was highly active in each of these distinct breast models, demonstrating equal or greater efficacy compared to any other regimen tested in studies of over 700 tumor-bearing mice. This regimen even exhibited activity in tumors selected for resistance to another effective chemotherapy agent, lapatinib, in HER2+ models. These results demonstrate the utility of credentialed murine models for large-scale efficacy testing of diverse anti-cancer regimens, and predict combinations of PI3K/mTOR and MEK inhibitors will demonstrate anti-tumor activity in a wide-range of human malignancies. 16 array samples

2012-08-21 | E-GEOD-35722 | biostudies-arrayexpress

Immune impact of neoadjuvant chemo/radio-therapy in the pancreatic cancer microenvironment

Project description:Pancreatic ductal adenocarcinoma (PDAC) has dismal five-year survival (<9%). We examined the impact of neoadjuvant FOLFIRINOX alone or in combination with radiation therapy (conventional radiotherapy, XRT, or stereotactic body radiotherapy, SBRT) on immunologically relevant genes in the PDAC tumor microenvironment (TME). We hypothesize conventional therapies may induce immune alterations in the TME that can be leveraged to enhance the efficacy of immunotherapy in PDAC. PDAC patients who underwent upfront surgical resection or who received neoadjuvant FOLFIRINOX with or without neoadjuvant radiotherapy followed by surgical resection were selected for study. The expression of 730 immunologically relevant transcripts was quantitated using the Nanostring PanCancer immune profiling panel (Platform GPL19965). This analysis identified189 genes that were differentially expressed at the RNA level on the basis of neoadjuvant therapy. On average specimens were obtained 6.6-17.0 weeks after the conclusion of neoadjuvant therapy, depending on treatment group. These data provide insight into the immunological effects of standard of care neoadjuvant therapy for resectable/borderline-resectable PDAC. This work provides data to guide strategic new combination therapies for pancreatic cancer.

2019-04-09 | GSE129492 | GEO

Genes activated by 5-aza-dC (DAC) in pancreatic (KPC-Brca1) cancer-associated fibroblasts (CAFs)

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy. Treatment of a short-term explant culture of cancer-associated fibroblasts (CAFs) from a KPC-Brca1 mouse pancreatic carcinoma, with 2 micromolar 5-aza-dC (decitabine; DAC) for 48 hours. The experiment includes 3 replicate plates untreated and 3 replicates treated.

2013-01-01 | E-GEOD-42364 | biostudies-arrayexpress

Genes activated by 5-aza-dC (DAC) in pancreatic cancer (KPC-Brca1) epithelial cells

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy. Treatment of a short-term explant culture of malignant epithelial cells from a KPC-Brca1 mouse pancreatic carcinoma, with 0.5 micromolar 5-aza-dC (decitabine; DAC) for 48 hours. The experiment includes 3 replicate plates untreated and 3 replicates treated.

2013-01-01 | E-GEOD-42365 | biostudies-arrayexpress

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