Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) shows gene expression patterns associated to immune checkpoint inhibitors response

Pantaleo, Maria Abbondanza; Tarantino, Giuseppe; Agostinelli, Claudio; Urbini, Milena; Nannini, Margherita; Saponara, Maristella; Castelli, Chiara; Stacchiotti, Silvia; Fumagalli, Elena; Gatto, Lidia; Santini, Donatella; Leo, Antonio De; Marafioti, Teresa; Akarca, Ayse U.; Sabattini, Elena; Pession, Andrea; Ardizzoni, Andrea; Indio, Valentina; Astolfi, Annalisa

doi:10.1080/2162402x.2019.1617588

Cited by 44 publications

(66 citation statements)

References 39 publications

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“…We cannot exclude that the grade of GIST, which was not included in this analysis, may have affected the immunological parameters as described in this study. 22 Notwithstanding the aforementioned shortcomings, this study provides an unprecedented and in-depth analysis of multiple STS subtypes with respect to CD8+ TILs and immune microenvironments and argues for validation of our main findings in larger cohorts of selected STS subtypes.…”

Section: Open Accessmentioning

confidence: 75%

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Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes

Klaver

Rijnders

Oostvogels

et al. 2020

J Immunother Cancer

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IntroductionLocal T-cell immunity is recognized for its contribution to the evolution and therapy response of various carcinomas. Here, we investigated characteristics of tumor-infiltrating lymphocytes (TILs), as well as T-cell evasive mechanisms in different soft tissue sarcoma (STS) subtypes.MethodsLiposarcoma, gastrointestinal stromal tumor (GIST), leiomyosarcoma, myxofibrosarcoma and pleomorphic sarcomas were assessed for T-cell numbers and phenotypes using flow cytometry. Next-generation sequencing was used to analyze T-cell receptor repertoire, mutational load, immune cell frequencies, and expression of immune-related genes.ResultsGIST, myxofibrosarcoma and pleomorphic sarcoma showed high numbers of CD8+ TILs, with GIST having the lowest fraction of effector memory T cells. These TILs coexpress the immune checkpoints PD1, TIM3, and LAG3 in myxofibrosarcoma and pleomorphic sarcoma, yet TILs coexpressing these checkpoints were near negligible in GIST. Fractions of dominant T-cell clones among STS subtypes were lowest in GIST and liposarcoma, whereas mutational load was relatively low in all STS subtypes. Furthermore, myeloid-derived cells and expression of the costimulatory ligands CD86, ICOS-L and 41BB-L were lowest in GIST when compared with other STS subtypes.ConclusionSTS subtypes differ with respect to number and phenotypical signs of antitumor responsiveness of CD8+ TILs. Notably, GIST, myxofibrosarcoma and pleomorphic sarcoma harbor high numbers of CD8+ T cells, yet in the GIST microenvironment, these T cells are less differentiated and non-exhausted, which is accompanied with a relatively low expression of costimulatory ligands.

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Section: Open Accessmentioning

confidence: 75%

“…In silico analyses using this STS subtype have demonstrated gene expression patterns associated with immune checkpoint inhibitor responses. 22 Studies treating metastasized GIST with nivolumab alone or in combination with ipilimumab are currently pending (NCT02880020).…”

Section: Introductionmentioning

confidence: 99%

Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes

Klaver

Rijnders

Oostvogels

et al. 2020

J Immunother Cancer

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“…Preoperative knowledge of risk classification can provide valuable information for evaluating the adequacy of surgical resection and the need for adjuvant treatment [5][6][7]. Ultrasound or CT-guided needle biopsy of GISTs for immunological analysis as an easy-to-perform method is commonly used in clinical practice [8]. However, biopsy before operation is not recommended for most GIST patients who can be completely resected [9], and a small amount of pathological tissues in some patients with preoperative biopsy indications fails to meet the need for accurate diagnosis [10].…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a nomogram based on CT images and 3D texture analysis for preoperative prediction of the malignant potential in gastrointestinal stromal tumors

2020

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Background: Gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal tumors of the digestive system, are treated varyingly according to the malignancy. The purpose of this study is to develop and validate a nomogram for preoperative prediction of the malignant potential in patients with GIST. Methods: A total of 440 patients with pathologically confirmed GIST after surgery in our hospital from January 2011 to July 2019 were retrospectively analyzed. They were randomly divided into the training set (n = 308) and validation set (n = 132). CT signs and texture features of each patient were analyzed and predictive model were developed using the least absolute shrinkage and selection operator (lasso) regression. Then a nomogram based on selected parameters was developed. The predictive effectiveness of nomogram was evaluated by the area under receiver operating characteristic (ROC) curve (AUC). Concordance index (C-index) and calibration plots were formulated to evaluate the reliability and accuracy of the nomogram by bootstrapping based on internal (training set) and external (validation set) validity. The clinical application value of the nomogram was determined through the decision curve analysis (DCA).Results: Totally 156 GIST patients with low-malignant (very low and low risk) and 284 ones with high-malignant potential (intermediate and high risk) are enrolled in this study. The prediction nomogram consisting of size, cystoid variation and meanValue had an excellent discrimination both in training and validation sets (AUCs (95% confidence interval(CI)): 0.935 (0.908, 0.961), 0.933 (0.892, 0.974); C-indices (95% CI): 0.941 (0.912, 0.956), 0.935 (0.901, 0.982); sensitivity: 81.4, 90.6%; specificity: 75.0, 75.7%; accuracy: 88.0, 88.6%, respectively). The calibration curves indicated a good consistency between the actual observation and nomogram prediction for differentiating GIST malignancy. Decision curve analysis demonstrated that the nomogram was clinically useful. Conclusion: This study presents a prediction nomogram that incorporates the CT signs and texture parameter, which can be conveniently used to facilitate the preoperative individualized prediction of malignancy in GIST patients.

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“…Vitiello et al(27) profiled 75 GIST (N= 37 KIT-and 24 PDGFRA-mutant) and observed significantly more immune cells present in the PDGFRA cohort. While Pantaleo et al(40) did not report genotype specific differences in immune infiltrates in their cohort, their sample size was significantly smaller (N= 21 KIT-and 10 PDGFRA-mutant), and some of these cases had IM treatment or were classified as unknown treatment status, which could potentially influence the number and activity of immune infiltrates.Our GIST kinome profiling identified several well-studied and established kinases, such as KIT, PRKCQ(29) and FGFR1(30), as significantly activated kinases in all GIST compared to normal tissue. In addition, our profiling identified other potential targets.…”

mentioning

confidence: 86%

“…Interestingly, these differences are partly due to elevated immune cell-associated kinases, including HCK, LCK, BTK, CSF1R and MERTK. Two recent reports(27,40) have used RNA-seq to obtain immune profiles in GIST. Vitiello et al(27) profiled 75 GIST (N= 37 KIT-and 24 PDGFRA-mutant) and observed significantly more immune cells present in the PDGFRA cohort.…”

mentioning

confidence: 99%

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Sharipova

Kozinova

et al. 2020

Preprint

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Gastrointestinal stromal tumor (GIST) management has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of receptor tyrosine kinase (RTK) inhibitors in advanced disease. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GIST, resistance remains a significant clinical obstacle.Development of effective strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes.PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT and PDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a monotherapy in the PDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

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Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) shows gene expression patterns associated to immune checkpoint inhibitors response

Abstract: Astolfi (2019) Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) shows gene expression patterns associated to immune checkpoint inhibitors response, OncoImmunology,

Cited by 44 publications

References 39 publications

Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes

Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes

Development and validation of a nomogram based on CT images and 3D texture analysis for preoperative prediction of the malignant potential in gastrointestinal stromal tumors

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

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