NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients

Abstract

Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (DBC low ) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This DBC low blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-a and anti-TRAIL mAb which reinstated innate immunity.

NKp30 isoforms and NKp46 transcripts in metastatic melanoma patients: Unique NKp30 pattern in rare melanoma patients with favorable evolution

“…The presence of high levels of NKp30C isoform in blood NK cells influences GIST patient's prognosis 11 and markedly impacted both event-free and OS, in two independent cohorts of metastatic GIST. 28 Low DBC values and low expression levels of NKp30A were identified in one-third of patients with dismal prognosis across molecular subtypes. This low DBC value in PBMC was associated with a pro-inflammatory and immunosuppressive tumor microenvironment.…”

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

“…11 In particular, the NK infiltrate predicts progression-free survival in GIST, and patients classified as immunological responders on the basis of NK-interferon levels showed a better survival while treated with imatinib. 12 Tumor-infiltrating lymphocytes (TIL) are the second most enriched immune cell population in GIST samples. 9,11,13,14 Balachandran et al demonstrated that CD8 + T cells contribute to antitumor effects of imatinib.…”

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

“…In these cases, the release of such ligands in the extracellular environment may represent an effective mechanism to dampen NK cell function, not only in physiologic immune interactions but also in tumor-driven escape strategies. 37-40 In this context, soluble ligands, endowed with suppressive capability, have been described for NKG2D and DNAM-1 activating receptors (sMICA, sULBPs, and sPVR) and for NKp30 (sB7H6 and sBAT3/BAG6). 32,33,35,41-50 On the other hand, extracellular ligands for NKp46 and NKp44 have been recently identified and demonstrated to have a positive effect on the NK cell function.…”