Targeting Endoglin Expressing Cells in the Tumor Microenvironment Does Not Inhibit Tumor Growth in a Pancreatic Cancer Mouse Model

Schoonderwoerd, Mark J.A.; Hakuno, Sarah K.; Sassen, Martijn; Kuhlemaijer, Eleonore B; Paauwe, Madelon; Slingerland, Marije; Fransen, Marieke F.; Hawinkels, Lukas J.A.C.

doi:10.2147/ott.s322276

Cited by 6 publications

(4 citation statements)

References 47 publications

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“…In contrast, evidence from multiple studies supports that apCAFs, which are observed in the CD105− group, cause immunosuppression by inhibiting T cells and are therefore considered pro-tumourigenic [33,[38][39][40]. However, the functional role of CD105+ and CD105− subsets is still not firmly established, as data from our group show that therapeutic inhibition or fibroblastspecific genetic deletion of CD105 did not affect mouse pancreatic tumour growth [41,42].…”

Section: The Different Colours Beyond Black and Whitecontrasting

confidence: 57%

The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer

Stouten

Montfoort

Hawinkels

2023

IJMS

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The lack of response to therapy in pancreatic ductal adenocarcinoma (PDAC) patients has contributed to PDAC having one of the lowest survival rates of all cancer types. The poor survival of PDAC patients urges the exploration of novel treatment strategies. Immunotherapy has shown promising results in several other cancer types, but it is still ineffective in PDAC. What sets PDAC apart from other cancer types is its tumour microenvironment (TME) with desmoplasia and low immune infiltration and activity. The most abundant cell type in the TME, cancer-associated fibroblasts (CAFs), could be instrumental in why low immunotherapy responses are observed. CAF heterogeneity and interactions with components of the TME is an emerging field of research, where many paths are to be explored. Understanding CAF–immune cell interactions in the TME might pave the way to optimize immunotherapy efficacy for PDAC and related cancers with stromal abundance. In this review, we discuss recent discoveries on the functions and interactions of CAFs and how targeting CAFs might improve immunotherapy.

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Section: The Different Colours Beyond Black and Whitecontrasting

confidence: 57%

The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer

Stouten

Montfoort

Hawinkels

2023

IJMS

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“…Although an increased percentage of tumor-infiltrating CD8 + cytotoxic T cells was observed after TRC105 treatment, this did not translate into changes in the tumor volume or mass. Furthermore, the combination of TRC105 and an α-PD-1 antibody therapies could not inhibit tumor growth in KPC [149]. These findings illustrate that, despite being abundantly present in the pancreatic tumor stroma, CD105 pos CAFs are not exclusively responsible for the tumor-promoting effects of CAFs.…”

Section: Cd105 + Cafsmentioning

confidence: 84%

“…The CD105-neutralizing antibody TRC105 (also known as Carotuximab) [147,148] reduced Smad1 phosphorylation in CAFs and decreased fibroblastmediated liver metastases [146]. However, in the context of pancreatic cancer, targeting CD105 pos CAFs could not inhibit tumor growth in the KPC model [149]. Although an increased percentage of tumor-infiltrating CD8 + cytotoxic T cells was observed after TRC105 treatment, this did not translate into changes in the tumor volume or mass.…”

Section: Cd105 + Cafsmentioning

confidence: 99%

A Quick Guide to CAF Subtypes in Pancreatic Cancer

Brichkina,

Polo,

Sharma

et al. 2023

Cancers

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Pancreatic cancer represents one of the most desmoplastic malignancies and is characterized by an extensive deposition of extracellular matrix. The latter is provided by activated cancer-associated fibroblasts (CAFs), which are abundant cells in the pancreatic tumor microenvironment. Many recent studies have made it clear that CAFs are not a singular cellular entity but represent a multitude of potentially dynamic subgroups that affect tumor biology at several levels. As mentioned before, CAFs significantly contribute to the fibrotic reaction and the biomechanical properties of the tumor, but they can also modulate the local immune environment and the response to targeted, chemo or radiotherapy. As the number of known and emerging CAF subgroups is steadily increasing, it is becoming increasingly difficult to keep up with these developments and to clearly discriminate the cellular subsets identified so far. This review aims to provide a helpful overview that enables readers to quickly familiarize themselves with field of CAF heterogeneity and to grasp the phenotypic, functional and therapeutic distinctions of the various stromal subpopulations.

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“…Primary fibroblasts and the hPS1 pancreatic stellate cell (PSC) line [ 15 ] (kindly provided by H. Kocher, University of London, London, England) were cultured in Dulbecco’s modified Eagle’s medium (DMEM)/F12 (Thermo Fisher Scientific) supplemented with 8% fetal calf serum (FCS), 100 IU/mL penicillin and 100 μg/mL streptomycin (all Thermo Fisher Scientific). Murine fibroblasts from pancreatic KPC tumors were isolated and cultured as described previously [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

Gastrointestinal cancer-associated fibroblasts expressing Junctional Adhesion Molecule-A are amenable to infection by oncolytic reovirus

et al. 2022

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Gastrointestinal (GI) cancers are characterized by extensive tumor stroma that both promotes tumor progression and acts as a physical barrier for adjacent tumor cells, limiting the effect of current treatment modalities. Oncolytic virotherapy is currently investigated in clinical trials as a novel therapeutic agent for different malignancies of the GI tract, but it is largely unknown whether these viruses can also target the tumor stroma. Here, we investigated the tropism of two commonly studied OVs, adenovirus and reovirus, towards primary GI fibroblasts from human oesophageal, gastric, duodenal and pancreatic carcinomas (N = 36). GI fibroblasts were susceptible to type 3 Dearing (T3D) strain R124 and bioselected mutant reovirus (jin-3) infection but not oncolytic adenovirus (Ad5-Δ24). Efficient infection and apoptosis of human and mouse GI cancer-derived fibroblasts by these reoviruses was partially dependent on the expression of the reovirus entry receptor, Junctional Adhesion Molecule-A (JAM-A). Moreover, human GI cancer organoid-fibroblast co-cultures showed higher overall infectivity when containing JAM-A expressing fibroblasts as compared to JAM-A negative fibroblasts, indicating a potential role of JAM-A expressing fibroblasts for viral dissemination. We further show that JAM-A is not only necessary for efficient reovirus infection of fibroblasts but also partially mediates reovirus-induced apoptosis, dependent on signaling through the C-terminal PDZ-domain of JAM-A. Altogether, our data show the presence of JAM-A expressing fibroblasts in both human and murine GI cancers that are amenable to infection and induction of apoptosis by reovirus, extending the potential anti-cancer actions of reovirus with stromal targeting.

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Targeting Endoglin Expressing Cells in the Tumor Microenvironment Does Not Inhibit Tumor Growth in a Pancreatic Cancer Mouse Model

Cited by 6 publications

References 47 publications

The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer

The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer

A Quick Guide to CAF Subtypes in Pancreatic Cancer

Gastrointestinal cancer-associated fibroblasts expressing Junctional Adhesion Molecule-A are amenable to infection by oncolytic reovirus

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