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Published on: February 5, 2020
Association of PTPRD/PTPRT Mutation With Better Clinical Outcomes in NSCLC Patients Treated With Immune Checkpoint
Xiaoyan Wang1, Bingchen Wu2, Zhengqing Yan3
1Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, China.
Abstract:
The common gamma receptor-dependent cytokines and their JAK-STAT pathways play important roles in T cell immunity and have been demonstrated to be related with response to immune checkpoint blockades (ICBs). PTPRD and PTPRT are phosphatases involved in JAK-STAT pathway. However, their clinical significance for non-small cell lung cancer (NSCLC) treated with ICBs is still unclear. Genomic and survival data of NSCLC patients administrated with anti-PD-1/PD-L1 or anti-CTLA-4 antibodies (Rizvi2015; Hellmann2018; Rizvi2018 Samstein2019) were retrieved from publicly accessible data. Genomic, survival and mRNA data of 1007 patients with NSCLC were obtained from The Cancer Genome Atlas (TCGA). PTPRD/PTPRT mutation was significantly associated with better progression-free survival (PFS) in three independent Rizvi2015, Hellmann2018 and Rizvi2018 cohorts. The median PFS for PTPRD/PTPRT mutant-type vs. wild-type NSCLC patients were not reached vs. 6.3 months (Rizvi2015, HR = 0.16; 95% CI, 0.02-1.17; P=0.03), 24.0 vs. 5.4 months (Hellmann2018, HR, 0.49; 95% CI, 0.26-0.94; P=0.03), 5.6 vs. 3.0 months (Rizvi2018, HR = 0.64; 95% CI, 0.44-0.92; P=0.01) and 6.8 vs. 3.5 months (Pooled cohort, HR, 0.54; 95% CI, 0.39-0.73; P<0.0001) respectively. PTPRD/PTPRT mutation was an independent predictive factor for PFS in pooled cohort (P = 0.01). Additionally, PTPRD/PTPRT mutation associated with better overall survival (OS) in Samstein2019 cohort (19 vs. 10 months, P=0.03). While similar clinical benefits were not observed in patients without ICBs treatment (TCGA cohort, P=0.78). In the further exploratory analysis, PTPRD/PTPRT mutation was significantly associated with increased tumor mutation burden and higher mRNA expression of JAK1 and STAT1. Gene Set Enrichment Analysis revealed prominent enrichment of signatures related to antigen processing and presentation in patients with PTPRD/PTPRT mutation. This work suggested that PTPRD/PTPRT mutation might be a potential positive predictor for ICBs in NSCLC. These results need to be further confirmed in future.
Insights
Mutations in PTPRD and PTPRT genes are linked to improved outcomes for non-small cell lung cancer (NSCLC) patients treated with immune checkpoint blockades (ICBs). These PTPRD/PTPRT mutations may serve as a predictive biomarker for ICB therapy response in NSCLC.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Common gamma receptor-dependent cytokines and JAK-STAT pathways are crucial for T cell immunity and influence response to immune checkpoint blockades (ICBs).
- Protein tyrosine phosphatases PTPRD and PTPRT are involved in the JAK-STAT pathway, but their role in non-small cell lung cancer (NSCLC) treated with ICBs remains unclear.
Purpose of the Study:
- To investigate the clinical significance of PTPRD and PTPRT mutations in NSCLC patients undergoing ICB therapy.
- To explore the association of PTPRD/PTPRT mutations with tumor mutation burden, gene expression, and immune response pathways.
Main Methods:
- Retrieved genomic and survival data for NSCLC patients treated with anti-PD-1/PD-L1 or anti-CTLA-4 antibodies from independent cohorts (Rizvi2015, Hellmann2018, Rizvi2018, Samstein2019).
- Analyzed data from 1007 NSCLC patients from The Cancer Genome Atlas (TCGA) for genomic, survival, and mRNA expression.
- Performed mutation analysis, survival analysis (progression-free survival and overall survival), and Gene Set Enrichment Analysis (GSEA).
Main Results:
- PTPRD/PTPRT mutations were significantly associated with better progression-free survival (PFS) across multiple independent cohorts and a pooled cohort.
- PTPRD/PTPRT mutation was identified as an independent predictive factor for PFS in NSCLC patients treated with ICBs.
- Patients with PTPRD/PTPRT mutations showed improved overall survival (OS) in one cohort and no significant benefit in patients without ICB treatment.
- Exploratory analysis revealed that PTPRD/PTPRT mutations correlate with increased tumor mutation burden, higher JAK1/STAT1 mRNA expression, and enriched antigen processing and presentation pathways.
Conclusions:
- PTPRD/PTPRT mutations may serve as a potential positive predictive biomarker for ICB therapy in NSCLC.
- The findings suggest a link between PTPRD/PTPRT mutations, enhanced anti-tumor immunity, and improved response to ICBs.
- Further validation studies are warranted to confirm the predictive value of PTPRD/PTPRT mutations in NSCLC patients receiving ICBs.
