Identification of Novel Prognostic Biomarkers Relevant to Immune Infiltration in Lung Adenocarcinoma

Overview

Journal Front Genet

Date 2022 May 16

PMID 35571056

Authors

Zhi Xia

Xueyao Rong

ZiYu Dai

Dongbo Zhou

Affiliations

Soon will be listed here.

Abstract

Programmed death ligand-1 (PD-L1) is a biomarker for assessing the immune microenvironment, prognosis, and response to immune checkpoint inhibitors in the clinical treatment of lung adenocarcinoma (LUAD), but it does not work for all patients. This study aims to discover alternative biomarkers. Public data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) were used to determine the gene modules relevant to tumor immunity. Protein-protein interaction (PPI) network and GO semantic similarity analyses were applied to identify the module hub genes with functional similarities to PD-L1, and we assessed their correlations with immune infiltration, patient prognosis, and immunotherapy response. Immunohistochemistry (IHC) and hematoxylin and eosin (H&E) staining were used to validate the outcome at the protein level. We identified an immune response-related module, and two hub genes (PSTPIP1 and PILRA) were selected as potential biomarkers with functional similarities to PD-L1. High expression levels of PSTPIP1 and PILRA were associated with longer overall survival and rich immune infiltration in LUAD patients, and both were significantly high in patients who responded to anti-PD-L1 treatment. Compared to PD-L1-negative LUAD tissues, the protein levels of PSTPIP1 and PILRA were relatively increased in the PD-L1-positive tissues, and the expression of PSTPIP1 and PILRA positively correlated with the tumor-infiltrating lymphocytes. We identified PSTPIP1 and PILRA as prognostic biomarkers relevant to immune infiltration in LUAD, and both are associated with the response to anti-PD-L1 treatment.

Citing Articles

Wan P, Zhong L, Yu L, Shen C, Shao X, Chen S Front Immunol. 2024; 15:1384633.

PMID: 38799454 PMC: 11117069. DOI: 10.3389/fimmu.2024.1384633.

References

Teng F, Meng X, Kong L, Mu D, Zhu H, Liu S . Tumor-infiltrating lymphocytes, forkhead box P3, programmed death ligand-1, and cytotoxic T lymphocyte-associated antigen-4 expressions before and after neoadjuvant chemoradiation in rectal cancer. Transl Res. 2015; 166(6):721-732.e1. DOI: 10.1016/j.trsl.2015.06.019. View

Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman D . IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017; 127(8):2930-2940. PMC: 5531419. DOI: 10.1172/JCI91190. View

Marcos T, Ruiz-Martin V, de la Puerta M, Trinidad A, Rodriguez M, de la Fuente M . Proline-serine-threonine phosphatase interacting protein 1 inhibition of T-cell receptor signaling depends on its SH3 domain. FEBS J. 2014; 281(17):3844-54. DOI: 10.1111/febs.12912. View

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G . The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2014; 26(2):259-71. PMC: 6267863. DOI: 10.1093/annonc/mdu450. View

Hayano A, Komohara Y, Takashima Y, Takeya H, Homma J, Fukai J . Programmed Cell Death Ligand 1 Expression in Primary Central Nervous System Lymphomas: A Clinicopathological Study. Anticancer Res. 2017; 37(10):5655-5666. DOI: 10.21873/anticanres.12001. View

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

Gibney G, Weiner L, Atkins M . Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016; 17(12):e542-e551. PMC: 5702534. DOI: 10.1016/S1470-2045(16)30406-5. View

Ophir Y, Duev-Cohen A, Yamin R, Tsukerman P, Bauman Y, Gamliel M . PILRα binds an unknown receptor expressed primarily on CD56bright and decidual-NK cells and activates NK cell functions. Oncotarget. 2016; 7(27):40953-40964. PMC: 5173034. DOI: 10.18632/oncotarget.8397. View

Hirsch F, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K . PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol. 2016; 12(2):208-222. DOI: 10.1016/j.jtho.2016.11.2228. View

10.

Janssen W, Grobarova V, Leleux J, Jongeneel L, van Gijn M, van Montfrans J . Proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) controls immune synapse stability in human T cells. J Allergy Clin Immunol. 2018; 142(6):1947-1955. DOI: 10.1016/j.jaci.2018.01.030. View

11.

Teng M, Ngiow S, Ribas A, Smyth M . Classifying Cancers Based on T-cell Infiltration and PD-L1. Cancer Res. 2015; 75(11):2139-45. PMC: 4452411. DOI: 10.1158/0008-5472.CAN-15-0255. View

12.

Tang H, Wang Y, Chlewicki L, Zhang Y, Guo J, Liang W . Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade. Cancer Cell. 2016; 29(3):285-296. PMC: 4794755. DOI: 10.1016/j.ccell.2016.02.004. View

13.

Sun Y, Senger K, Baginski T, Mazloom A, Chinn Y, Pantua H . Evolutionarily conserved paired immunoglobulin-like receptor α (PILRα) domain mediates its interaction with diverse sialylated ligands. J Biol Chem. 2012; 287(19):15837-50. PMC: 3346071. DOI: 10.1074/jbc.M111.286633. View

14.

Morris L, Riaz N, Desrichard A, Senbabaoglu Y, Hakimi A, Makarov V . Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival. Oncotarget. 2016; 7(9):10051-63. PMC: 4891103. DOI: 10.18632/oncotarget.7067. View

15.

Dong Z, Wu S, Liao R, Huang S, Wu Y . Potential biomarker for checkpoint blockade immunotherapy and treatment strategy. Tumour Biol. 2016; 37(4):4251-61. DOI: 10.1007/s13277-016-4812-9. View

16.

Teng F, Meng X, Kong L, Yu J . Progress and challenges of predictive biomarkers of anti PD-1/PD-L1 immunotherapy: A systematic review. Cancer Lett. 2017; 414:166-173. DOI: 10.1016/j.canlet.2017.11.014. View

17.

Travis W . Pathology of lung cancer. Clin Chest Med. 2011; 32(4):669-92. DOI: 10.1016/j.ccm.2011.08.005. View

18.

Gowrishankar K, Gunatilake D, Gallagher S, Tiffen J, Rizos H, Hersey P . Inducible but not constitutive expression of PD-L1 in human melanoma cells is dependent on activation of NF-κB. PLoS One. 2015; 10(4):e0123410. PMC: 4386825. DOI: 10.1371/journal.pone.0123410. View

19.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

20.

Bald T, Landsberg J, Lopez-Ramos D, Renn M, Glodde N, Jansen P . Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation. Cancer Discov. 2014; 4(6):674-87. DOI: 10.1158/2159-8290.CD-13-0458. View