Differential expression of individual transcript variants of PD-1 and PD-L2 genes on Th-1/Th-2 status is guaranteed for prognosis prediction in PCNSL

Abstract

In current molecular medicine, next-generation sequencing (NGS) for transcript variant detection and multivariable analyses are valid methods for evaluating gene expression, cancer mechanisms, and prognoses of patients. We conducted RNA-sequencing on samples from patients with primary central nervous system lymphoma (PCNSL) using NGS and performed multivariable analysis on gene expression data and correlations focused on Th-1/Th-2 helper T cell balance and immune checkpoint to identify diagnosis/prognosis markers and cancer immune pathways in PCNSL. We selected 84 transcript variants to limit the analysis range for Th-1/Th-2 balance and stimulatory and inhibitory checkpoints in 31 PCNSLs. Of these, 21 highly-expressed transcript variants were composed of the formulas for prognoses based on Th-1/Th-2 status and checkpoint activities. Using formulas, Th-1^low, Th-2^high, and stimulatory checkpoint^high resulted in poor prognoses. Further, Th-1^highTh-2^low was associated with good prognoses. On the other hand, CD40-001^high and CD70-001^high as stimulatory genes, and LAG3-001^high, PDCD1 (PD-1)-001/002/003^high, and PDCD1LG2 (PD-L2)-201^low as inhibitory genes were associated with poor prognoses. Interestingly, Th-1^highTh-2^low and Th-1^lowTh-2^high were correlated with stimulatory checkpoint^low as CD70-001^low and inhibitory checkpoint^low as HAVCR2 (TIM-3)-001^low and PDCD1LG2-001/201^low, respectively. Focused on the inhibitory checkpoint, specific variants of CD274 (PD-L1)-001 and PDCD1-002 served severe hazard ratios. In particular, PDCD1-002^high by a cut off score was associated with poor prognoses, in addition to PDCD1-001/003^high, PDCD1LG2-201^low, and LAG3-001^high. These results mainly suggest that expression of transcript variants of PDCD1 and PDCD1LG2 on the Th-1/Th-2 balance enable prognostic prediction in PCNSL. This study provides insights for development of molecular target therapies and identification of diagnosis/prognosis markers in PCNSL.