Over-Expression and Prognostic Significance of HHLA2, a New Immune Checkpoint Molecule, in Human Clear Cell Renal Cell Carcinoma.

Zhen Zhang,Jinyan Liu,Yi Zhang,Xingxing Zang,Fangxia Guan,Chaoqi Zhang,Dan Wang,Lifeng Li,Feng Li,Damini Chand

doi:10.3389/fcell.2020.00280

Abstract

HHLA2, a newly identified B7 family member, regulates T cell functions. However, the expression and prognostic value of HHLA2 in solid tumors is ill defined. This study aimed to reveal the expression landscape of HHLA2 in various solid tumors, and to evaluate its prognostic value in kidney clear cell carcinoma (KIRC). Using The Cancer Genome Atlas (TCGA) database, we investigated the expression pattern of HHLA2 across 22 types of cancer. HHLA2 and CD8 protein expression was determined via immunohistochemistry (IHC). KIRC-specific findings were further analyzed with R software and the prognostic value was validated on tissue microarrays. HHLA2 was widely expressed in cancers at both the mRNA and protein levels. Among all tested tumors, KIRC showed the highest transcript level of HHLA2, and HHLA2 levels were significantly higher in tumor tissues than in matched normal samples, as evidenced by both TCGA and IHC data. HHLA2 was also positively correlated with survival rates in KIRC based on TCGA and clinical data. Receiver operating characteristic curves data showed the prognostic value of HHLA2 for patients with KIRC in TCGA. Moreover, HHLA2 was positively correlated with immune-related genes, while HHLA2 and CD8 expression exhibited a consistent trend in KIRC tumor samples. In conclusion, HHLA2 is highly expressed in KIRC and predicts a favorable survival outcome, highlighting that it may work as a potential target for KIRC therapy.

Highlights

MATERIALS AND METHODSRenal cell carcinoma (RCC) accounts for 3% of adult malignant tumors and ranks as the most lethal of all urologic cancers (Ferlay et al, 2015)
Consistent with The Cancer Genome Atlas (TCGA) data, HHLA2 was widely expressed in 12 types of solid tumors in protein level, including kidney renal cell carcinoma (KIRC), rectum adenocarcinoma (READ), colon adenocarcinoma (COAD), breast invasive carcinoma (BRCA), pancreatic adenocarcinoma (PAAD), lung adenocarcinoma (LUAD), esophageal carcinoma (ESCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), STAD, bladder urothelial carcinoma (BLCA), UCEC, and THCA (Figure 1B)
We explored the mechanisms underlying the up-regulation of HHLA2, which predicts a favorable outcome for KIRC

Summary

Introduction

MATERIALS AND METHODSRenal cell carcinoma (RCC) accounts for 3% of adult malignant tumors and ranks as the most lethal of all urologic cancers (Ferlay et al, 2015). In one mechanism of tumor evasion from the immune system, tumor cells express coinhibitory ligands that result in T cell exhaustion and blunt the immune response (Chen et al, 2018; Zhang et al, 2020) By targeting this phenomenon, immune checkpoint blockade therapy (ICBT), can unleash the breaks in the immune system and induce long-lasting responses (Hato et al, 2014; Marin-Acevedo et al, 2018a). Immune checkpoint blockade therapy (ICBT), can unleash the breaks in the immune system and induce long-lasting responses (Hato et al, 2014; Marin-Acevedo et al, 2018a) With these advances in immunotherapy, patients with KIRC have been treated with PD-1 inhibitors; the limited expression of PD-Ll limits application of this therapy in the clinic (Shi et al, 2019). Identifying a more suitable target in KIRC to improve immunotherapy efficacy is necessary

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