Transcriptional profiling of parental and immunotherapy-resistant mouse pancreatic tumor cells
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ORGANISM(S): Mus musculus
PROVIDER: GSE158077 | GEO | 2021/08/24
REPOSITORIES: GEO
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Project description:Transcriptional profiling of parental and immunotherapy-resistant mouse pancreatic tumor cells
| PRJNA663895 | ENA
Project description:The paper describes a model on the size of pancreatic tumour.
Created by COPASI 4.25 (Build 207)
This model is described in the article:
Modeling Pancreatic Cancer Dynamics with Immunotherapy
Xiaochuan Hu, Guoyi Ke and Sophia R.-J. Jang
Bulletin of Mathematical Biology (2019) 81:1885–1915
Abstract:
We develop a mathematical model of pancreatic cancer that includes pancreatic cancer cells, pancreatic stellate cells, effector cells and tumor-promoting and tumor- suppressing cytokines to investigate the effects of immunotherapies on patient survival. The model is first validated using the survival data of two clinical trials. Local sen- sitivity analysis of the parameters indicates there exists a critical activation rate of pro-tumor cytokines beyond which the cancer can be eradicated if four adoptive trans- fers of immune cells are applied. Optimal control theory is explored as a potential tool for searching the best adoptive cellular immunotherapies. Combined immunother- apies between adoptive ex vivo expanded immune cells and TGF-β inhibition by siRNA treatments are investigated. This study concludes that mono-immunotherapy is unlikely to control the pancreatic cancer and combined immunotherapies between anti-TGF-β and adoptive transfers of immune cells can prolong patient survival. We show through numerical explorations that how these two types of immunotherapies are scheduled is important to survival. Applying TGF-β inhibition first followed by adoptive immune cell transfers can yield better survival outcomes.
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2024-09-02 | BIOMD0000000744 | BioModels
Project description:This is a mathematical model of pancreatic cancer that includes descriptions of pancreatic cancer cells, pancreatic stellate cells, effector cells and tumor-promoting and tumor-suppressing cytokines to investigate the effects of immunotherapies on patient survival.
2024-09-02 | BIOMD0000000792 | BioModels
Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.
2015-11-21 | E-GEOD-75233 | biostudies-arrayexpress
Project description:Pancreatic cancer is one of the deadliest cancers in humans and is yet refractory to immunotherapy. Identifying factors that can sensitize pancreatic cancer to immune cells may thus hold the key to improving immunotherapy efficacy. Herein, by pooled CRISPR activation screening, we find that the transcriptional regulator Mcrs1 (Microspherule protein 1) is pivotal to the immune sensitivity of pancreatic cancer cells, with elevated Mcrs1 expression inducing enhanced immune responses and tumor suppression in mice.
2024-10-14 | GSE239364 | GEO
Project description:Pancreatic cancer is one of the deadliest cancers in humans and is yet refractory to immunotherapy. Identifying factors that can sensitize pancreatic cancer to immune cells may thus hold the key to improving immunotherapy efficacy. Herein, by pooled CRISPR activation screening, we find that the transcriptional regulator Mcrs1 (Microspherule protein 1) is pivotal to the immune sensitivity of pancreatic cancer cells, with elevated Mcrs1 expression inducing enhanced immune responses and tumor suppression in mice.
2024-10-14 | GSE239360 | GEO
Project description:Pancreatic cancer is one of the deadliest cancers in humans and is yet refractory to immunotherapy. Identifying factors that can sensitize pancreatic cancer to immune cells may thus hold the key to improving immunotherapy efficacy. Herein, by pooled CRISPR activation screening, we find that the transcriptional regulator Mcrs1 (Microspherule protein 1) is pivotal to the immune sensitivity of pancreatic cancer cells, with elevated Mcrs1 expression inducing enhanced immune responses and tumor suppression in mice.
2024-10-14 | GSE239359 | GEO
Project description:Pancreatic cancer is one of the deadliest cancers in humans and is yet refractory to immunotherapy. Identifying factors that can sensitize pancreatic cancer to immune cells may thus hold the key to improving immunotherapy efficacy. Herein, by pooled CRISPR activation screening, we find that the transcriptional regulator Mcrs1 (Microspherule protein 1) is pivotal to the immune sensitivity of pancreatic cancer cells, with elevated Mcrs1 expression inducing enhanced immune responses and tumor suppression in mice.
2024-10-14 | GSE239358 | GEO
Project description:Pancreatic cancer is one of the deadliest cancers in humans and is yet refractory to immunotherapy. Identifying factors that can sensitize pancreatic cancer to immune cells may thus hold the key to improving immunotherapy efficacy. Herein, by pooled CRISPR activation screening, we find that the transcriptional regulator Mcrs1 (Microspherule protein 1) is pivotal to the immune sensitivity of pancreatic cancer cells, with elevated Mcrs1 expression inducing enhanced immune responses and tumor suppression in mice.
2024-10-14 | GSE239357 | GEO
Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME. Between July 2008 and September 2012, 59 patients were enrolled into an ongoing study of an irradiated, allogeneic GM-CSF-secreting pancreatic tumor vaccine (GVAX) administered intradermally either alone or in combination with immune modulatory doses of cyclophophamide (Cy) as neoadjuvant and adjuvant treatment for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Patients were randomized 1:1:1 to 3 treatment arms. In Arm A, patients received GVAX alone; in Arm B, patients received GVAX plus a single intravenous dose of Cy at 200 mg/m2 1 day prior to each vaccination; in Arm C, patients received GVAX plus oral Cy at 100 mg once daily for 1 week on and 1 week off. Up to 6 GVAX treatments were administered and all of the patients remained in their initial treatment arms throughout the duration of the study. All 59 of the patients received the 1st GVAX treatment 2 weeks +/-4 days prior to surgery. Formalin-fixed paraffin-embedded (FFPE) tissue blocks of surgically resected PDAC were obtained from the pathology archive. FFPE tissue blocks from each subject were stained by H&E immediately before the vaccine therapy-induced lymphoid aggregates were microdissected . To better understand the functional status of these vaccine therapy induced lymphoid aggregate structures, gene microarray analysis on RNA isolated from microdissected lymphoid aggregates was performed. Gene expression was compared among samples grouped according to patient overall survival, post-vaccination induction of enhanced mesothelin-specific T cell responses in peripheral blood lymphocytes (PBL), and the intratumoral CD8+ T effector to FoxP3+ Treg ratio. Post-vaccination induction of enhanced mesothelin-specific T cell responses has been reported to correlate with longer survival in patients treated with Panc GVAX.
2014-08-05 | E-GEOD-52171 | biostudies-arrayexpress