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Nature Reviews. Clinical Oncology Jul 2023In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape... (Review)
Review
In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape of CCA has been characterized and tumour subsets with distinct immune microenvironments have been defined using molecular approaches. Among these subsets, the identification of 'immune-desert' tumours that are relatively devoid of immune cells emphasizes the need to consider the tumour immune microenvironment in the development of immunotherapy approaches. Progress has also made in identifying the complex heterogeneity and diverse functions of cancer-associated fibroblasts in this desmoplastic cancer. Assays measuring circulating cell-free DNA and cell-free tumour DNA are emerging as clinical tools for detection and monitoring of the disease. Molecularly targeted therapy for CCA has now become a reality, with three drugs targeting oncogenic fibroblast growth factor receptor 2 (FGFR2) fusions and one targeting neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1) obtaining regulatory approval. By contrast, immunotherapy using immune-checkpoint inhibitors has produced disappointing results in patients with CCA, underscoring the requirement for novel immune-based treatment strategies. Finally, liver transplantation for early stage intrahepatic CCA under research protocols is emerging as a viable therapeutic option in selected patients. This Review highlights and provides in-depth information on these advances.
Topics: Humans; Bile Duct Neoplasms; Cholangiocarcinoma; Immunotherapy; Cancer-Associated Fibroblasts; Bile Ducts, Intrahepatic; Tumor Microenvironment
PubMed: 37188899
DOI: 10.1038/s41571-023-00770-1 -
Cancer Discovery Feb 2024Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy because of its aggressive nature and the paucity of effective treatment options. Almost all...
UNLABELLED
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy because of its aggressive nature and the paucity of effective treatment options. Almost all registered drugs have proven ineffective in addressing the needs of patients with PDAC. This is the result of a poor understanding of the unique tumor-immune microenvironment (TME) in PDAC. To identify druggable regulators of immunosuppressive TME, we performed a kinome- and membranome-focused CRISPR screening using orthotopic PDAC models. Our data showed that receptor-interacting protein kinase 2 (RIPK2) is a crucial driver of immune evasion of cytotoxic T-cell killing and that genetic or pharmacologic targeting of RIPK2 sensitizes PDAC to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy, leading to prolonged survival or complete regression. Mechanistic studies revealed that tumor-intrinsic RIPK2 ablation disrupts desmoplastic TME and restores MHC class I (MHC-I) surface levels through eliminating NBR1-mediated autophagy-lysosomal degradation. Our results provide a rationale for a novel combination therapy consisting of RIPK2 inhibition and anti-PD-1 immunotherapy for PDAC.
SIGNIFICANCE
PDAC is resistant to almost all available therapies, including immune checkpoint blockade. Through in vivo CRISPR screen, we identified that RIPK2 plays a crucial role in facilitating immune evasion by impeding antigen presentation and cytotoxic T-cell killing. Targeting tumor-intrinsic RIPK2 either genetically or pharmacologically improves PDAC to anti-PD-1 immunotherapy. See related commentary by Liu et al., p. 208 . This article is featured in Selected Articles from This Issue, p. 201.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Immunotherapy; T-Lymphocytes, Cytotoxic; Protein Kinases; Tumor Microenvironment
PubMed: 37824278
DOI: 10.1158/2159-8290.CD-23-0584 -
The Lancet. Gastroenterology &... Aug 2023Accumulation of fibroblasts in the premalignant or malignant liver is a characteristic feature of liver cancer, but has not been therapeutically leveraged despite... (Review)
Review
Accumulation of fibroblasts in the premalignant or malignant liver is a characteristic feature of liver cancer, but has not been therapeutically leveraged despite evidence for pathophysiologically relevant roles in tumour growth. Hepatocellular carcinoma is a largely non-desmoplastic tumour, in which fibroblasts accumulate predominantly in the pre-neoplastic fibrotic liver and regulate the risk for hepatocellular carcinoma development through a balance of tumour-suppressive and tumour-promoting mediators. By contrast, cholangiocarcinoma is desmoplastic, with cancer-associated fibroblasts contributing to tumour growth. Accordingly, restoring the balance from tumour-promoting to tumour-suppressive fibroblasts and mediators might represent a strategy for hepatocellular carcinoma prevention, whereas in cholangiocarcinoma, fibroblasts and their mediators could be leveraged for tumour treatment. Importantly, fibroblast mediators regulating hepatocellular carcinoma development might exert opposite effects on cholangiocarcinoma growth. This Review translates the improved understanding of tumour-specific, location-specific, and stage-specific roles of fibroblasts and their mediators in liver cancer into novel and rational therapeutic concepts.
Topics: Humans; Carcinoma, Hepatocellular; Fibroblasts; Liver Neoplasms; Cholangiocarcinoma; Bile Ducts, Intrahepatic; Bile Duct Neoplasms
PubMed: 37385282
DOI: 10.1016/S2468-1253(23)00111-5 -
Nature Communications Aug 2023The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the...
The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define mechanisms involved, here we treat established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). Depletion of FAP CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR T cells and to anti-PD-1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape by reducing myeloid cell accumulation and increasing endogenous CD8 T cell and NK cell infiltration. These data provide strong rationale for combining tumor stroma- and malignant cell-targeted therapies to be tested in clinical trials.
Topics: Humans; Immunosuppression Therapy; Immunotherapy; Cell Movement; Pancreatic Neoplasms; CD8-Positive T-Lymphocytes
PubMed: 37607999
DOI: 10.1038/s41467-023-40850-5 -
Gut Aug 2023Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune...
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8 T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC.
DESIGN
Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or quiescent pancreatic stellate cells (qPSC) were exposed to conditional media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was performed. IL-17A/F-, IL-17RA-, RAG1-deficient and mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models.
RESULTS
Increased abundance of Tc17 cells highly correlated with reduced survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF differentiation as assessed by the expression of iCAF-associated genes via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured with Tc17-iCAF displayed enhanced proliferation and increased expression of genes implicated in proliferation, metabolism and protection from apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in and mice, respectively. Finally, -expressed by fibroblasts was required for Tc17-driven tumour growth in vivo.
CONCLUSIONS
We identified Tc17 as a novel protumourigenic CD8 T-cell subtype in PDAC, which accelerated tumour growth via IL-17RA-dependent stroma modification. We described a crosstalk between three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC progression, which resulted in poor prognosis for patients.
Topics: Humans; CD8-Positive T-Lymphocytes; Cancer-Associated Fibroblasts; Interleukin-17; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Homeodomain Proteins
PubMed: 36759154
DOI: 10.1136/gutjnl-2022-327855 -
Seminars in Cell & Developmental Biology Mar 2024Many cancers begin with the formation of a small nest of transformed cells that can remain dormant for years. Thrombospondin-1 (TSP-1) initially promotes dormancy by... (Review)
Review
Many cancers begin with the formation of a small nest of transformed cells that can remain dormant for years. Thrombospondin-1 (TSP-1) initially promotes dormancy by suppressing angiogenesis, a key early step in tumor progression. Over time, increases in drivers of angiogenesis predominate, and vascular cells, immune cells, and fibroblasts are recruited to the tumor mass forming a complex tissue, designated the tumor microenvironment. Numerous factors, including growth factors, chemokine/cytokine, and extracellular matrix, participate in the desmoplastic response that in many ways mimics wound healing. Vascular and lymphatic endothelial cells, and cancer-associated pericytes, fibroblasts, macrophages and immune cells are recruited to the tumor microenvironment, where multiple members of the TSP gene family promote their proliferation, migration and invasion. The TSPs also affect the immune signature of tumor tissue and the phenotype of tumor-associated macrophages. Consistent with these observations, expression of some TSPs has been established to correlate with poor outcomes in specific types of cancer.
Topics: Humans; Thrombospondins; Endothelial Cells; Tumor Microenvironment; Neoplasms; Extracellular Matrix
PubMed: 37286406
DOI: 10.1016/j.semcdb.2023.05.010 -
Clinical and Translational Medicine Dec 2023Cancer-associated fibroblasts (CAFs) are potential targets for cancer therapy. Due to the heterogeneity of CAFs, the influence of CAF subpopulations on the progression...
Single-cell and spatial transcriptomics reveal POSTN cancer-associated fibroblasts correlated with immune suppression and tumour progression in non-small cell lung cancer.
BACKGROUND
Cancer-associated fibroblasts (CAFs) are potential targets for cancer therapy. Due to the heterogeneity of CAFs, the influence of CAF subpopulations on the progression of lung cancer is still unclear, which impedes the translational advances in targeting CAFs.
METHODS
We performed single-cell RNA sequencing (scRNA-seq) on tumour, paired tumour-adjacent, and normal samples from 16 non-small cell lung cancer (NSCLC) patients. CAF subpopulations were analyzed after integration with published NSCLC scRNA-seq data. SpaTial enhanced resolution omics-sequencing (Stereo-seq) was applied in tumour and tumour-adjacent samples from seven NSCLC patients to map the architecture of major cell populations in tumour microenvironment (TME). Immunohistochemistry (IHC) and multiplexed IHC (mIHC) were used to validate marker gene expression and the association of CAFs with immune infiltration in TME.
RESULTS
A subcluster of myofibroblastic CAFs, POSTN CAFs, were significantly enriched in advanced tumours and presented gene expression signatures related to extracellular matrix remodeling, tumour invasion pathways and immune suppression. Stereo-seq and mIHC demonstrated that POSTN CAFs were in close localization with SPP1 macrophages and were associated with the exhausted phenotype and lower infiltration of T cells. POSTN expression or the abundance of POSTN CAFs were associated with poor prognosis of NSCLC.
CONCLUSIONS
Our study identified a myofibroblastic CAF subpopulation, POSTN CAFs, which might associate with SPP1 macrophages to promote the formation of desmoplastic architecture and participate in immune suppression. Furthermore, we showed that POSTN CAFs associated with cancer progression and poor clinical outcomes and may provide new insights on the treatment of NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cancer-Associated Fibroblasts; Lung Neoplasms; Macrophages; Gene Expression Profiling; Tumor Microenvironment; Cell Adhesion Molecules
PubMed: 38115703
DOI: 10.1002/ctm2.1515