Multiple intratumoral sources of kit ligand promote gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit or PDGFRA receptor. While highly effective, tyrosine kinase inhibitors (TKIs) are not curative. The natural ligand for the Kit receptor is Kit ligand (KitL), which exists in both soluble and membrane-bound forms.

Csf1r or Mer inhibition delays liver regeneration via suppression of Kupffer cells.

Introduction: Murine Kupffer cells (KCs) comprise CD11bhi and F4/80hi subsets. Tissue-resident macrophages are known to express the tyrosine kinase receptors colony-stimulating factor 1 receptor (Csf1r) and Mer. However, the expression of Csf1r and Mer on KC subsets and the importance of these tyrosine kinases during liver regeneration (LR) are unknown.

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs.

Macrophages and CD8 T Cells Mediate the Antitumor Efficacy of Combined CD40 Ligation and Imatinib Therapy in Gastrointestinal Stromal Tumors.

Tyrosine kinase inhibition of gastrointestinal stromal tumors (GIST) is effective but typically culminates in resistance and is rarely curative. Immunotherapy has potential application to GIST, as we previously showed that T-cell checkpoint blockade increases the antitumor effects of imatinib. Here, we showed that ligation of CD40 using an agonistic antibody (anti-CD40) activated tumor-associated macrophages (TAMs) in a knock-in mouse model of GIST harboring a germline mutation in exon 11.

ETV4 collaborates with Wnt/β-catenin signaling to alter cell cycle activity and promote tumor aggressiveness in gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common sarcoma, often resulting from a or platelet-derived growth factor receptor alpha () mutation. The lineage transcription factor ETV1 is expressed similarly in GISTs regardless of malignant potential. Although the related transcription factor ETV4 has been associated with metastasis and tumor progression in other cancers, its role in GIST is unknown.

Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor.

Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown.

Wnt/β-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a or mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain.

Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab.

A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic. A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment. Dose escalation cohorts received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12 weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg twice daily).

PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors.

Purpose: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs.