Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer

被引：12

作者：

Kula, Agnieszka ^{[1
]}

Dawidowicz, Miriam ^{[1
]}

Mielcarska, Sylwia ^{[2
]}

Kiczmer, Pawel ^{[3
]}

Skiba, Hanna ^{[3
]}

Krygier, Malgorzata ^{[3
]}

Chrabanska, Magdalena ^{[3
]}

Piecuch, Jerzy ^{[4
]}

Szrot, Monika ^{[4
]}

Robotycka, Julia ^{[2
]}

Ochman, Blazej ^{[2
]}

Strzalkowska, Bogumila ^{[2
]}

Czuba, Zenon ^{[5
]}

Swietochowska, Elzbieta ^{[2
]}

Waniczek, Dariusz ^{[1
]}

机构：

[1] Med Univ Silesia, Fac Med Sci Zabrze, Dept Oncol Surg, PL-41808 Katowice, Poland

[2] Med Univ Silesia, Fac Med Sci Zabrze, Dept Med & Mol Biol, 19 Jordana, PL-41800 Zabrze, Poland

[3] Med Univ Silesia, Fac Med Sci Zabrze, Dept & Chair Pathomorphol, 13-15 3 Maja, PL-41800 Zabrze, Poland

[4] Med Univ Silesia, Fac Med Sci Zabrze, Dept Gen & Bariatr Surg & Emergency Med, PL-41808 Katowice, Poland

[5] Med Univ Silesia, Fac Med Sci Zabrze, Dept Microbiol & Immunol, PL-40055 Katowice, Poland

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2023年 / 24卷 / 06期

关键词：

colorectal cancer; immune checkpoint; HHLA2; MSI; immunotherapy; B7; FAMILY; SURVIVAL; MEMBER; RESISTANCE; BIOMARKERS;

D O I：

10.3390/ijms24065876

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The study aimed to investigate correlations between HHLA2 levels and parameters, including microsatellite instability (MSI) status, CD8+ cells, and histopathological features: budding, tumor-infiltrating lymphocytes (TILs), TNM scale, grading, cytokines, chemokines, and cell signaling moleculesin colorectal cancer (CRC). Furthermore, the immune infiltration landscape and HHLA2-related pathways in colorectal cancer using available online datasets were analyzed. The study included 167 patients diagnosed with CRC. Expression of HHLA2 was detected by immunohistochemistry method (IHC) and enzyme-linked immunosorbent assay (ELISA). The IHC was used to evaluate the MSI and CD8+ status. The budding and TILs were measured using a light microscope. The concentrations of cytokines, chemokines, and cell signaling molecules were measured to analyze the data by the Bio-Plex Pro Human cytokine screening panel, 48 cytokine assay, and principal component analysis (PCA). Geneset enrichment analysis (GSEA) was conducted to identify HHLA2-related pathways. The biological function of HHLA2 was predicted by Gene Ontology (GO). Analysis of the immune infiltration landscape of HHLA2 in colorectal cancer was made by the web-based tool Camoip. High HHLA2 expression was detected in CRC tumor tissues compared to the adjacent noncancerous tissues. The percentage of HHLA2-positive tumors was 97%. GSEA and GO showed that HHLA2 upregulation correlated with cancer-related pathways and several biological functions. Tumor-infiltrating lymphocytes score correlated positively with IHC HHLA2 expression level percentage. There was a negative correlation between HHLA2, anti-tumor cytokines and pro-tumor growth factors. This study provides a valuable insight into the role of HHLA2 in CRC. We reveal the role of HHLA2 expression as well as a stimulatory and inhibitory immune checkpoint in colorectal cancer. Further research may verify the therapeutic values of the HHLA2-KIR3DL3/TMIGD2 pathway in colorectal cancer.

引用

页数：21

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