Translating Knowledge About the Immune Microenvironment of Gastrointestinal Stromal Tumors into Effective Clinical Strategies

Chantharasamee, Jomjit; Adashek, Jacob J.; Wong, Karlton; Eckardt, Mark A.; Chmielowski, Bartosz; Dry, Sarah M.; Eilber, Fritz C.; Singh, Arun S.

doi:10.1007/s11864-020-00806-z

Cited by 4 publications

(5 citation statements)

References 52 publications

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“…The symptoms may be vague, mostly bleeding and anemia related to mucosal ulceration. Abdominal pain, discomfort, and new mass may lead to the discovery of the tumor (1,2,3). A variety of symptoms were encountered in our series such as bleeding, abdominal pain, and dyspepsia but interestingly, some tumors were incidentally found during obesity surgery.…”

Section: Discussionmentioning

confidence: 74%

“…The oncogenic mutations in these genes result in activation of the tyrosine kinase receptor, which regulates proliferation and growth (4). The mutations in c-kit or platelet-derived growth factor receptor alpha (PDGFRA) exist in almost 85-90% of GIST cases (3). The remaining 10% cases are succinate dehydrogenase-deficient GISTs, NF1-associated GISTs, translocation-associated GISTs, and, BRAF V600E-mutated GISTs (3,5,6,7).…”

Section: Introductionmentioning

confidence: 99%

“…The mutations in c-kit or platelet-derived growth factor receptor alpha (PDGFRA) exist in almost 85-90% of GIST cases (3). The remaining 10% cases are succinate dehydrogenase-deficient GISTs, NF1-associated GISTs, translocation-associated GISTs, and, BRAF V600E-mutated GISTs (3,5,6,7). Hirota et al reported expression of CD117 (c-KIT) immunohistochemically is a key diagnostic marker for GISTs in the year 1998 (8).…”

Section: Introductionmentioning

confidence: 99%

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Gastrointestinal Stromal Tümörlerin Klinikopatolojik Özellikleri ve Literatürün Gözden Geçirilmesi: Tek Merkez Deneyimi

Coşkun

2022

Konuralp Tıp Dergisi

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Objective: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasias of the gastrointestinal system (GIS). The malignancy potential of GISTs may vary ranging from indolent tumors to progressive malignant tumors. This study aims to define clinicopathological and immunohistochemical features of GISTs diagnosed in our institute with a review of the literature. Method: A total of 28 GIST cases were included in the study. The Hematoxylin&Eosin stained slides of surgical resection materials and cell blocks and immunohistochemistry performed slides were reviewed by a pathologist. The immunohistochemical expression with CD117, DOG-1, CD34, SMA, and S100 was scored between 0 and 3 points according to staining intensity. Descriptive statistics were used in the study. The demographic data, prognostic histopathological, and immunohistochemical findings are evaluated with the literature indications. Result: Eleven of the cases were male and seventeen were female. The age range was 18-88. The most common site of GISTs was the stomach, followed by the small intestine, colorectal region, and, esophagus. Twenty of the tumors were resected surgically, four were endoscopic biopsy material and four were fine-needle aspiration biopsies. The tumor size in measurable materials ranged from 0,2 to 22 cm. The mitotic count in 50 HPF ranges from 0 to 10. Seven of the GISTs were high grade and the remaining 21 were low grade. The majority of the cases were composed of spindle cells, 3 were epithelioid and 3 were the mixed type with spindle and epitheloid cells. Conclusion: A variety of criteria has been proposed to estimate the malignancy potential of GISTs and predict prognosis but definite prognostic criteria remain uncertain. Further studies with larger series of GISTs consisting of different types of biopsy materials may help define criteria to predict prognosis precisely.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gastrointestinal Stromal Tümörlerin Klinikopatolojik Özellikleri ve Literatürün Gözden Geçirilmesi: Tek Merkez Deneyimi

Coşkun

2022

Konuralp Tıp Dergisi

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“…Notably, PDGFRA -mutant GISTs are characterized by the strongest immune-signature and immune-pathway enrichment compared to other GIST molecular subtypes, including KIT mutant and SDH-deficient GISTs [ 23 , 24 , 25 ]. Conversely, our study supports that D842V GISTs represent a tumor subset with distinctive biological behavior compared to other GISTs with non-D842V PDGFRA mutations.…”

Section: Discussionmentioning

confidence: 99%

miRNA Expression May Have Implications for Immunotherapy in PDGFRA Mutant GISTs

Ravegnini

Nannini

Indio

et al. 2022

IJMS

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Gastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5–7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is correlated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different biological behavior of this GIST subset.

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“…The role of immunotherapy in sarcomas is growing fast with no current standard of care. If our current understanding of the immune response in GIST remains limited, several data suggested that the exploitation of immune system may be clinically interesting [ 14 ]. The presence of tumor-infiltrating immune cells such as macrophages, CD8+ T-cells, T-reg, and NK-cells has been described in clinical samples [ 15 , 16 , 17 , 18 ] and associated with prognosis [ 17 ], imatinib response [ 15 , 19 , 20 ], and potential vulnerability to immune checkpoint inhibitors [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

CSPG4 Expression in GIST Is Associated with Better Prognosis and Strong Cytotoxic Immune Response

Nonneville

Finetti

Picard

et al. 2022

Cancers

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The treatment of gastrointestinal stromal tumors (GIST) must be improved through the development of more reliable prognostic factors and of therapies able to overcome imatinib resistance. The immune system represents an attractive tool. CSPG4, a cell surface proteoglycan, emerged as a potential therapeutic target for immune therapy in different cancers, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in sarcomas. CSPG4 expression has never been studied in GIST. We analyzed CSPG4 mRNA expression data of 309 clinical GIST samples profiled using DNA microarrays and searched for correlations with clinicopathological and immune features. CSPG4 expression, higher in tumors than normal digestive tissues, was heterogeneous across tumors. High expression was associated with AFIP low-risk, gastric site, and localized stage, and independently with longer postoperative disease-free survival (DFS) in localized stage. The correlations between CSPG4 expression and immune signatures highlighted a higher anti-tumor immune response in “CSPG4-high” tumors, relying on both the adaptive and innate immune system, in which the boost of NK cells by CSPG4-CAR.CIKs might be instrumental, eventually combined with immune checkpoint inhibitors. In conclusion, high CSPG4 expression in GIST is associated with better DFS and offers an immune environment favorable to a vulnerability to CAR.CIKs.

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Translating Knowledge About the Immune Microenvironment of Gastrointestinal Stromal Tumors into Effective Clinical Strategies

Cited by 4 publications

References 52 publications

Gastrointestinal Stromal Tümörlerin Klinikopatolojik Özellikleri ve Literatürün Gözden Geçirilmesi: Tek Merkez Deneyimi

Gastrointestinal Stromal Tümörlerin Klinikopatolojik Özellikleri ve Literatürün Gözden Geçirilmesi: Tek Merkez Deneyimi

miRNA Expression May Have Implications for Immunotherapy in PDGFRA Mutant GISTs

CSPG4 Expression in GIST Is Associated with Better Prognosis and Strong Cytotoxic Immune Response

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