Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors

Abstract

The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.

Shaping of NK Cell Responses by the Tumor Microenvironment

“…These data suggest that certain solid malignancies are infiltrated by a significant number of NK cells. Those include renal cell carcinoma [108] and gastrointestinal sarcoma (GIST) [33], where frequencies of NK cells among tumor-infiltrating leukocytes are found to be higher than in peripheral blood. Renal cell carcinoma-infiltrating NK cells displayed reduced cytotoxicity and increased surface levels of NKG2A/CD94 inhibitory receptor complex [108].…”

“…Renal cell carcinoma-infiltrating NK cells displayed reduced cytotoxicity and increased surface levels of NKG2A/CD94 inhibitory receptor complex [108]. In GIST patients, NK cells were found to express predominantly the immunosuppressive isoform of the NKp30 receptor named NKp30c [33]. Compared to NKp30 isoforms a and b, which dominate in healthy individuals, triggering of NK30c with tumor cells or iDCs that express NKp30 ligands led to increased IL-10 production and diminished release of IFN-γ.…”

“…Three different isoforms of NKp30 were described. The final outcome of NKp30 activation depends on the NKp30 isoform expressed on the surface and can result in a quantitatively and qualitatively different response of NK cells [33].…”

Natural killer cell mediated immunosurveillance of pediatric neuroblastoma

“…4 Moreover, the phenotype of circulating NK cells related to NKp30 isoform expression predicted the longterm effects of imatinib therapy in GIST independently of the mutational status of c-KIT exon 11. 5,6 The NCR3 gene (alternative protein name: CD337) encodes three isoforms of the NKp30 protein that are generated by alternative splicing and that have rather Hence, NKp30A and NKp30B may be considered as immunostimulatory, while NKp30C is immunosuppressive. 5 Importantly, it appears that there are major differences in the NKp30 isoform expression pattern among different individuals that are at least in part explained by polymorphisms in the NKp30 locus (and hence have a genetic basis) and which might also be influenced by gene methylation patterns (which implies an epigenetic mechanism).…”

“…5,6 The NCR3 gene (alternative protein name: CD337) encodes three isoforms of the NKp30 protein that are generated by alternative splicing and that have rather Hence, NKp30A and NKp30B may be considered as immunostimulatory, while NKp30C is immunosuppressive. 5 Importantly, it appears that there are major differences in the NKp30 isoform expression pattern among different individuals that are at least in part explained by polymorphisms in the NKp30 locus (and hence have a genetic basis) and which might also be influenced by gene methylation patterns (which implies an epigenetic mechanism). Although the NKp30 isoform expression profile can be modulated by culture of NK cells in the presence of DNA demethylating agents, the relative proportion of the three distinct isoforms are relatively constant.…”