Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice

Duperret, Elizabeth K.; Trautz, Aspen; Ammons, Dylan T.; Perales‐Puchalt, Alfredo; Wise, Megan C.; Yan, Jian; Reed, Charles C.; Weiner, David B.

doi:10.1158/1078-0432.ccr-17-2033

Cited by 101 publications

(78 citation statements)

References 45 publications

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“…Seprase‐inhibition experiments demonstrated that functional seprase on the surface of TP cells promotes their intravasation into the bloodstream as iCTCs and formation of micrometastases in the lung. Consistent with our conclusion on the therapeutic potential of seprase inhibition, other works have recently demonstrated the role of seprase/FAP inhibition in immunotherapy . A full preclinical study to demonstrate survival benefit is therefore warranted to address the therapeutic potential of seprase or iCTCs as a whole in the near future.…”

Section: Discussionsupporting

confidence: 89%

“…Consistent with our conclusion on the therapeutic potential of seprase inhibition, other works have recently demonstrated the role of seprase/FAP inhibition in immunotherapy. [33][34][35] A full preclinical study to demonstrate survival benefit is therefore warranted to address the therapeutic potential of seprase or iCTCs as a whole in the near future.…”

Section: Discussionmentioning

confidence: 99%

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The propensity of invasive circulating tumor cells (iCTCs) in metastatic progression and therapeutic responsiveness

et al. 2019

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Circulating tumor cells (CTCs) are important clinical indicators of metastatic progression and treatment efficacy. However, because of their low number and heterogeneity, reliable patient‐derived CTC models are not readily available. We report here the isolation and characterization of the invasive population of CTCs, iCTCs, from blood of 10 patients with epithelial ovarian cancer (EOC) and one pancreatic cancer patient based on the avidity of tumor cells toward an artificial collagen‐based adhesion matrix (CAM), in comparison with tumor progenitor (TP) cells isolated from tumor cell lines, tumors and ascites from EOC patients. CAM‐avid cells identified to be iCTCs were indistinguishable with TP cells using either functional CAM uptake or surface markers (seprase and CD44). In addition, iCTCs were characterized using peritoneal and spontaneous metastasis models in vivo to evaluate their metastatic propensity and therapeutic response. TP cells and iCTCs had a doubling time of about 34‐42 hours. TP cells were rare (<3.5%) in most patient‐derived specimens, however, iCTCs emigrated into blood, at a high frequency, 64.2% (n = 49). Approximately 500 patient‐derived iCTCs recapitulated formation of iCTCs in mouse blood and formed micrometastases in the liver and/or lung, a degree of metastatic spread equivalent to the inoculation of 5 × 10 5 bulk tumor cells isolated from ascites and tumors. iCTCs were shown to be novel therapeutic targets for blocking metastasis using the reduced formation of iCTCs and micrometastases by RNAi, peptides, and monoclonal antibodies against seprase.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

The propensity of invasive circulating tumor cells (iCTCs) in metastatic progression and therapeutic responsiveness

et al. 2019

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“…Interestingly, the development of novel immunotherapies also offers new routes to deplete CAFs. For instance, strategies for vaccination against the FAP antigen were shown to reduce tumour growth, decrease metastatic burden, and overcome immune tolerance in mouse models of colon, lung, and breast cancer [94,95]. In addition, FAP-specific chimeric antigen receptor T (CAR T) cells were shown to induce an immune response against FAP-expressing cells, while also reducing tumour growth in pancreatic and lung cancer [96][97][98] (Figure 3C).…”

Section: Depleting Cafsmentioning

confidence: 99%

CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

et al. 2019

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Cancer-associated fibroblasts (CAFs) are one of the most significant components in the tumour microenvironment (TME), where they can perform several protumourigenic functions. Several studies have recently reported that CAFs are more heterogenous and plastic than was previously thought. As such, there has been a shift in the field to study CAF subpopulations and the emergent functions of these subsets in tumourigenesis. In this review, we explore how different aspects of CAF heterogeneity are defined and how these manifest in multiple cancers, with a focus on pancreatic ductal adenocarcinoma (PDAC). We also discuss therapeutic approaches to selectively target protumourigenic CAF functions, while avoiding normal fibroblasts, providing insight into the future of stromal targeting for the treatment of PDAC and other solid tumours. Cancer-Associated Fibroblasts: Major Players in Pancreatic Tumourigenesis PDAC is one of the most lethal solid malignancies, with a 5-year survival rate of $9% [1]. Widespread fibrotic desmoplasia is one of the cornerstones of PDAC development, progression, metastasis, and treatment resistance, where stromal components of the TME can have fundamental and integrated roles in promoting tumourigenesis [2-6]. This extensive desmoplastic reaction is characterised by the recruitment and activation of CAFs, aberrant extracellular matrix (ECM) deposition and remodelling, tumour angiogenesis, altered blood supply, as well as increased inflammation coupled with altered (and often impaired) innate and adaptive immune responses [4,5,7-9]. CAFs are one of the most prominent and active components in the pancreatic TME [4,5]. During early tumour initiation, reciprocal tumour-stroma signalling drives the reprogramming of mesenchymal cells, such as pancreatic stellate cells (PSCs), into CAFs [6], after which they can perform numerous anti-and protumourigenic functions in the TME. For instance, PDAC CAFs are the chief source of fibrotic matrisomal components, such as collagens, hyaluronic acid (HA), and fibronectin, among others, as recently described by Tian et al. [10]. This fibrosis has downstream biomechanical and biochemical effects in the TME [11], including impaired drug efficacy due to reduced interfibrillar spacing in the interstitium, which leads to reduced vascular patency and poor immune cell infiltration [12-17]. Moreover, CAFs produce several chemokines, cytokines, growth factors, miRNAs, exosomes, and metabolites that can instruct cancer cells and other TME components to promote malignant biology [4,5]. Given the central role of CAFs in the TME, there have been several attempts to target them in combination with other therapeutic approaches, such as chemotherapy or immunotherapy, for the treatment of PDAC. Thus far, this treatment approach has been largely unsuccessful and, in some preclinical studies, harmful. This is best exemplified through the studies of Ö zdemir et al. [18] and Rhim et al. [19], which both found that depletion of CAFs in genetically engineered mouse models (GEMMs) of PDA...

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“…Moreover, it has already been shown, that via various mechanisms, CAFs can promote the evolution of a multidrug-resistant tumour phenotype [12]. Many studies reported that pharmacological modification of the crosstalk between CAFs and tumour cells can hamper metastasis and ameliorate survival, further highlighting the supportive function of CAFs upon metastatic dissemination [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Core–shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts

et al. 2020

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Background: Although accumulating evidence suggests that the crosstalk between malignant cells and cancerassociated fibroblasts (CAFs) actively contributes to tumour growth and metastatic dissemination, therapeutic strategies targeting tumour stroma are still not common in the clinical practice. Metal-based nanomaterials have been shown to exert excellent cytotoxic and anti-cancerous activities, however, their effects on the reactive stroma have never been investigated in details. Thus, using feasible in vitro and in vivo systems to model tumour microenvironment, we tested whether the presence of gold, silver or gold-core silver-shell nanoparticles exerts anti-tumour and metastasis suppressing activities by influencing the tumour-supporting activity of stromal fibroblasts. Results: We found that the presence of gold-core silver-shell hybrid nanomaterials in the tumour microenvironment attenuated the tumour cell-promoting behaviour of CAFs, and this phenomenon led to a prominent attenuation of metastatic dissemination in vivo as well. Mechanistically, transcriptome analysis on tumour-promoting CAFs revealed that silver-based nanomaterials trigger expressional changes in genes related to cancer invasion and tumour metastasis. Conclusions: Here we report that metal nanoparticles can influence the cancer-promoting activity of tumour stroma by affecting the gene expressional and secretory profiles of stromal fibroblasts and thereby altering their intrinsic crosstalk with malignant cells. This potential of metal nanomaterials should be exploited in multimodal treatment approaches and translated into improved therapeutic outcomes.

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Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice

Cited by 101 publications

References 45 publications

The propensity of invasive circulating tumor cells (iCTCs) in metastatic progression and therapeutic responsiveness

The propensity of invasive circulating tumor cells (iCTCs) in metastatic progression and therapeutic responsiveness

CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

Core–shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts

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