Comprehensive Assessment of PD-L1 and PD-L2 Dysregulation in Gastrointestinal Cancers

Abstract

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials&methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

Keywords::

• gastrointestinal cancers
• PD-L1
• PD-L2
• SP1
• survival
• tumor mutation burden

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2020-0093

Acknowledgments

The authors thank the patients and investigators who participated in UCSC, TCGA and GEO for providing data.

Financial&competing interests disclosure

This work was supported by the National Natural Science Foundation of China (Grant nos. 81602166 and 81672444), Sichuan Science and Technology Plan Project (2018JY0079), the Joint Funds of the Southwest Medical University&Luzhou (2016LZXNYD-T01, 2017LZXNYD-Z05 and 2017LZXNYD-J09) and the Science and Technology Foundation of Shenzhen (JCYJ20170307095620828). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Data sharing statement

All data generated or analyzed during this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Grant nos. 81602166 and 81672444), Sichuan Science and Technology Plan Project (2018JY0079), the Joint Funds of the Southwest Medical University&Luzhou (2016LZXNYD-T01, 2017LZXNYD-Z05 and 2017LZXNYD-J09) and the Science and Technology Foundation of Shenzhen (JCYJ20170307095620828). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.