Comprehensive analysis of tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2): A potential novel pan-cancer immune checkpoint

Abstract

Tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2) is encoded by TNFAIP8L2 and is a newly identified negative regulator of natural and acquired immunity that plays a critical function in maintaining immune homeostasis. Recently, CAR-NK immune cell therapy has been a focus of major research efforts as a novel cancer therapeutic strategy. TIPE2 is a potential checkpoint molecule for immune cell maturation and antitumor immunity that could be used as a novel NK cell-based immunotherapeutic approach. In this study, we explored the expression of TNFAIP8L2 across various tumor types and found that TNFAIP8L2 was highly expressed in most tumor types and correlated with prognosis. Survival analysis showed that TNFAIP8L2 expression was predictive of improved survival in cervical-squamous-cell-carcinoma (CESC), sarcoma (SARC) and skin-cutaneous-melanoma (SKCM). Conversely, TNFAIP8L2 expression predicted poorer survival in acute myeloid leukemia (LAML), lower-grade-glioma (LGG), kidney-renal-clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). Analysis of stemness features and immune cell infiltration indicated that TNFAIP8L2 was significantly associated with cancer stem cell index and increased macrophage and dendritic cell infiltration. Our data suggest that TNFAIP8L2 may be a novel immune checkpoint biomarker across different tumor types, particularly in LAML, LGG, KIRC and UVM, and may have further utility as a potential target for immunotherapy.

Keywords: BLCA, Bladder Urothelial Carcinoma; BRCA, Breast invasive carcinoma; CESC, Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, Cholangiocarcinoma; COAD, Colon adenocarcinoma; ESCA, Esophageal carcinoma; GBM, Glioblastoma multiforme; HNSC, Head and Neck squamous cell carcinoma; Immune cell infiltration; KICH, Kidney Chromophobe; KIRC, Kidney renal clear cell carcinoma; KIRP, Kidney renal papillary cell carcinoma; LAML, Acute Myeloid Leukemia; LGG, Lower Grade Glioma; LIHC, Liver hepatocellular carcinoma; LUAD, Lung adenocarcinoma; LUSC, Lung squamous cell carcinoma; MESO, Mesothelioma; New immune checkpoint; OV, Ovarian serous cystadenocarcinoma; PAAD, Pancreatic adenocarcinoma; PCPG, Pheochromocytoma and Paraganglioma; PRAD, Prostate adenocarcinoma; Pan-cancer; READ, Rectum adenocarcinoma; SARC, Sarcoma; SKCM, Skin Cutaneous Melanoma; STAD, Stomach adenocarcinoma; Stemness feature; TGCT, Testicular Germ Cell Tumor; THCA, Thyroid carcinoma; THYM, Thymoma; TIPE2; UCEC, Uterine Corpus Endometrial Carcinoma; UCS, Uterine Carcinosarcoma; UVM, Uveal Melanoma.

Graphical abstract

Fig. 1

TNFAIP8L2 expression in normal tissues. (A) TNFAIP8L2 RNA expression in healthy tissues or organs from the Human Protein Atlas project. Different colors correspond to different tissues and organs. (B) RNA expression of TNFAIP8L2 in healthy tissues or organs from the ConsensusPathDB database. (C) TIPE2 protein expression in healthy tissues or organs from the FANTOM5 dataset. (D-F) Single-cell analysis of TNFAIP8L2 expression in the bone marrow (D), spleen (E) and lymph nodes (F). The red point re[resented different cells in clusters. Clusters were showed in coded rank by number 0 – 9. The expressions of cells in different clusters were showed by histogram. (G) TNFAIP8L2 expression in all cells at the single cell level. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

TNFAIP8L2 expression in tumors. (A) UMAP analysis of TNFAIP8L2 expression using single-cell RNA sequencing data from HPA. Different colors means different clusters. (B) The significant cluster 4 associated with TNFAIP8L2 expression among all the clusters. (C) The top 15 nearest neighbours based on single cell type RNA expression. (D) TNFAIP8L2 expression in immune cells from the HPA database. Different colors correspond to the different immune cells. (E) TNFAIP8L2 expression in immune cells from the Monaco database. (F) Subcellular localization of TIPE2 by immunofluorescence microscopy. Red indicates microtubules; blue indicates the nucleus; green indicates TIPE2. (G) TNFAIP8L2 expression in cancers from TCGA and the GETx database. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Prognosis analysis of TNFAIP8L2 in tumors. (A) Forest tree analysis of TNFAIP8L2 in all types of cancer. The HRs are shown to the left of the figure. (B) Survival analysis of TNFAIP8L2 on OS in LAML, LGG, KIRC and UVM. (C) Survival analysis of TNFAIP8L2 on OS in SKCM, CESC and SARC. (D) The summary of survival analysis of TNFAIP8L2 on OS, DFI, PFI and DSS in all cancers. *, p < 0.05; **, p < 0.01; ***, p < 0.001. (E) Kaplan–Meier analysis on OS in AML, LGG, KIRC, UVM, SKCM, CESC and SARC by ENCORI.

Fig. 4

TNFAIP8L2 and clinical features in tumors. (A) The correlation of TNFAIP8L2 expression and age in cancers. (B) The expression value of TNFAIP8L2 between different genders in 7 tumors. Red indicates females and blue indicates males. (C) The relationship between disease grade and TNFAIP8L2 expression. Red = G3; blue = G4; Green = G2 and grey = G1. (D) The difference in TNFAIP8L2 expression at different stages of disease. Red = Stage III; blue = Stage IV; green = Stage II and grey = Stage I. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

TNFAIP8L2, CSCs index and immune infiltration in cancers. (A) The correlation of TNFAIP8L2 expression and CSCs index in cancers. The target cancer types are marked in red. (B) Immune infiltration of TNFAIP8L2 in six types of cancers. The correlation value was calculated by Pearson analysis. (C-D) Validation of immune infiltration with TNFAIP8L2 in all cancers using Timer2 (C) and xCELL (D). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)