Dataset Information

Activated gold-decorated nanoparticles enhance PD-1 blockade and promote cytotoxic T cell anti-tumor responses in cholangiocarcinoma

ABSTRACT: Immunotherapy has revolutionized cancer treatment over the past decade. However, in most solid tumors, its effectiveness is often impaired owing to immune-resistance mediated through the tumor microenvironment (TME). In fibrotic cancers such as cholangiocarcinoma (CCA), the extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) create a dense, rigid stroma that hinders immune cell infiltration and fosters immunosuppression. Overcoming these physical and biological barriers is critical to fully unleash the potential of immunotherapeutic approaches. Here, the combination of photothermal therapy (PTT) with gold-iron oxide nanoflowers (GIONFs) effectively reshapes the TME by reducing ECM stiffness and facilitating immune cell infiltration. The GIONF-mediated TME mechanical reprogramming in combination with PD-1 immune checkpoint blockade leads to T-cell activation and reduces the immunosuppressive CAF subset. In preclinical models, this combination approach significantly supported anti-tumor immune responses and improved tumor control. Our findings emphasize the therapeutic potential of reshaping the TME to overcome immunotherapy resistance in fibrotic tumors like CCA. Targeting both the ECM and immune checkpoints may therefore represent a promising strategy to improve the efficacy of immunotherapy against desmoplastic cancers.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cholangiocarcinoma Cell Line

SUBMITTER: Chiara guerrera

LAB HEAD: Chiara Guerrera

PROVIDER: PXD058542 | Pride | 2025-10-17

REPOSITORIES: Pride

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			Action	DRS
	240313_MiMI_nE_TTP_DIA_Liver_n1-4_prCISOLp_1_11445.d.7z	Other
	240313_MiMI_nE_TTP_DIA_Liver_n1-5_prCISOLp_2_11446.d.7z	Other
	240313_MiMI_nE_TTP_DIA_Liver_n1-5_prCISOLp_3_11447.d.7z	Other
	240313_MiMI_nE_TTP_DIA_Liver_n1-5_prCISOLp_4_11448.d.7z	Other
	240313_MiMI_nE_TTP_DIA_Liver_n1-5_prCISOLp_5_11449.d.7z	Other

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Publications

Laser-activated nanoparticles rewire tumor microenvironment enhancing PD-1 blockade and T cell response in cholangiocarcinoma.

Minini Mirko M Avveduto Giulio G Becharef Sonia S Meunier-Thaens Marie M Lekbaby Bouchra B Perez-Lazon Maria M Machado Alice A Guilbert Thomas T Lesieur Julie J Renault Gilles G Ceccacci Sara S Guerrera Ida Chiara IC Klein Christophe C Augustin Jérémy J Bazzi Rana R Roux Stephane S Pol Jonathan J Donnadieu Emmanuel E Gazeau Florence F Fouassier Laura L

Hepatology (Baltimore, Md.) 20251002

<h4>Background and aims</h4>Immunotherapy has continued to revolutionize cancer treatment, achieving remarkable progress over the past decade. However, in most solid tumors, its effectiveness is often impaired because of immune resistance driven by the tumor microenvironment (TME). In fibrotic cancers, such as cholangiocarcinoma (CCA), the extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) form a dense, rigid stroma that hinders immune cell infiltration and promotes immunosuppre ...[more]

PMID: 41037683

Similar Datasets

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.

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.

Project description:Cholangiocarcinoma (CCA) is a hepatobiliary malignancy with dismal prognosis. Currently available models fail to recapitulate the full complexity of CCA, particularly the desmoplastic environment and the interplay between cancer cells and the extracellular matrix (ECM). We aimed to study the role of epithelial tumor cells in ECM deposition and desmoplasia by designing a model encompassing primary epithelial CCA organoids (CCAOs) and native liver and tumor scaffolds obtained by decellularization Background & Aims: Cholangiocarcinoma (CCA) is a hepatobiliary malignancy with dismal prognosis. Currently available models fail to recapitulate the full complexity of CCA, particularly the desmoplastic environment and the interplay between cancer cells and the extracellular matrix (ECM). We aimed to study the role of epithelial tumor cells in ECM deposition and desmoplasia by designing a model encompassing primary epithelial CCA organoids (CCAOs) and native liver and tumor scaffolds obtained by decellularization. Results: Decellularization resulted in effective removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. When culturing CCAOs in CCA-M, compared to TFL-M and BME, the genome-wide gene expression profile much more resembled the transcriptome of primary CCA tumor tissue in vivo, with an accompanying increase in chemoresistance. CCAOs in decellularized matrix, both CCA-M and TFL-M, exhibited the formation of complex morphological structures, and revealed environment-dependent proliferation and migration dynamics, driven by the occurrence of epithelial-mesenchymal transition (EMT). CCA-M induced specific extracellular matrix protein production in CCAOs, such as fibronectin 1 (FN1), which is related to desmoplasia and patient survival. In TFL-M, lacking the desmoplastic environment, CCAOs were able to initiate a desmoplastic reaction directly through increased production of multiple collagen types. Conclusions: This improved model of cholangiocarcinoma, combining organoids and native extracellular matrix, recapitulates key components of CCA tumor biology, including transcriptome profiles, migration patterns, EMT, and ECM protein production. The increased production of extracellular matrix proteins suggests that epithelial tumor cells can contribute to their own desmoplastic environment.