PTPRD/PTPRT mutation correlates to treatment outcomes of immunotherapy and immune landscape in pan-cancers

Objective: PTPRD and PTPRT are phosphatases of the JAK-STAT pathway related to immunotherapy.However, the role and mechanism of PTPRD and PTPRT mutations in multiple cancers remains unclear.Methods: Clinical data and PTPRD/PTPRT mutation information from 12 cohorts were collected and classified as a discovery cohort and three validation cohorts. The association between PTPRD/PTPRT mutations and immunotherapeutic efficacy was analyzed. Then, the association between PTPRD/PTPRT mutation and immune profiles was analyzed using The Cancer Genome Atlas(TCGA) cohort.Results: A total of 2,392 patients across 20 cancer types were included in this study. Our results showed that patients harboring PTPRD/PTPRT mutation, especially co-mutations, had a significantly elevated response rate to immunotherapy in multiple cancers. Patients with PTPRD/PTPRT mutation had a higher objective response rate(ORR)(P=0.002), longer overall survival(OS)(P=0.005) and progression-free survival(PFS)(P=0.038).Importantly, the above findings were further verified in validation cohorts. In addition, we found that the PTPRD/PTPRT co-mutations(co-mut) subgroup exhibited an immune-activated phenotype, the wild-type subgroup tended to have an immune-desert phenotype, and the uni-mutation(uni-mut) subgroup might have an immune-mixed phenotype. Our further analyses suggested that combining programmed cell death ligand 1(PDL1) expression and PTPRD/PTPRT mutation can be used to screen patients who may benefit from immunotherapy.Conclusions: PTPRD/PTPRT mutation could serve as a potential predictive biomarker for cancer immunotherapy.

TRIM28 promotes the escape of gastric cancer cells from immune surveillance by increasing PD-L1 abundance

Immune checkpoint blockade(ICB)offers a new opportunity for treatment for gastric cancer(G.C.).Understanding the upstream regulation of immune checkpoints is crucial to further improve the efficacy of ICB therapy.Herein,using the CRISPR-Cas9-based genome-wide screening,we identified TRIM28 as one of the most significant regulators of PD-L1,a checkpoint protein,in G.C.cells.

SDCBP-AS1 destabilizesβ-catenin by regulating ubiquitination and SUMOylation of hnRNP K to suppress gastric tumorigenicity and metastasis

Background:Gastric cancer(GC)is among the most malignant tumors,yet the pathogenesis is not fully understood,especially the lack of detailed information about the mechanisms underlying long non-coding RNA(lncRNA)-mediated post-translational modifications.Here,the molecular mechanisms and clinical significance of the novel lncRNA syndecan-binding protein 2-antisense RNA 1(SDCBP2-AS1)in the tumorigenesis and progression of GC were investigated.Methods:The expression levels of SDCBP2-AS1 in 132 pairs of GC and adjacent normal tissues were compared,and the biological functions were assessed in vitro and in vivo.RNA pull-down and immunoprecipitation assays were conducted to clarify the interactions of SDCBP2-AS1 and heterogeneous nuclear ribonucleoprotein(hnRNP)K.RNA-sequencing,immunoprecipitation,immunofluorescence,and luciferase analyses were performed to investigate the functions of SDCBP2-AS1.Results:SDCBP2-AS1 was significantly downregulated in GC tissues and pre-dictive of poor patient prognosis.Silencing of SDCBP2-AS1 promoted the proliferation and migration of GC cells both in vitro and in vivo.Mechanically,SDCBP2-AS1 physically bound to hnRNP K to repress SUMOylation of hnRNP K and facilitated ubiquitination of hnRNP K andβ-catenin,thereby promoting the degradation ofβ-catenin in the cytoplasm.Silencing of SDCBP2-AS1 caused SUMOylation of hnRNP K and stabilizedβ-catenin activity,which altered tran-scription of downstream genes,resulting in tumorigenesis and metastasis of GC.Moreover,the knockdown of hnRNP K partially abrogated the effects of SDCBP2-AS1.Conclusions:SDCBP2-AS1 interacts with hnRNP K to suppress tumorigenesis and metastasis of GC and regulates post-transcriptional modifications of hnRNP K to destabilizeβ-catenin.These findings suggest SDCBP2-AS1 as a potential target for the treatment of GC.