RIPK3 modulates sarcoma through immune checkpoint HAVCR2

Sarcomas is a complex group of malignant diseasse with undetermined molecular mechanisms. Receptor interacting serine/threonine kinase 3 (RIPK3) is a necroptosis- and apoptosis-related marker that has been implicated in several immune-associated diseases and aggressive malignant tumours. In the present study, publicly available transcriptome sequencing data were collected from The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research To Generate Effective Treatments (TARGET) databases and extensive data mining was performed, focusing on RIPK3 and its potential function in the modulation of gene expression and signaling pathways, immune checkpoints and cell infiltration. Analysis of TCGA and TARGET data revealed 603 up- and 260 downregulated genes in the higher RIPK3 expression group compared with the lower RIPK3 expression groups, with transmembrane channel like 8 and transmembrane protein 97 as the top up- and downregulated genes, respectively. Further pathway analysis revealed that the overexpressed genes were enriched in 'cytokine-cytokine receptor interaction'. Higher RIPK3 was found to be associated with improved survival, the immune checkpoint gene hepatitis A virus cellular receptor 2 (HAVCR2) and an improved response to immune blockade therapy. The potential modulation of HAVCR2 expression by RIPK3 was confirmed by reverse transcription-quantiative PCR in KHOS and 143B human osteosarcoma cell lines. Immune cell infiltration analysis revealed that RIPK3 was positively associated with macrophage and monocyte infiltration, suggesting that RIPK3 executes its function through these immune cells. These findings led to the hypothesis that increased RIPK3 expression may result in improved survival, possibly by regulating the immune checkpoint HAVCR2. In conclusion, the present study comprehensively elucidated the RIPK3 profile with regard to sarcoma survival, transcriptome expression, immune checkpoint therapy and immune cell infiltration. These findings suggest that RIPK3 is potentially a therapeutic target for sarcoma.