HHLA2 promotes tumor progression by long non‑coding RNA H19 in human gallbladder cancer

Zhang, Yizhou; Li, Hanrong; Lv, Chao; Wu, Baokang; Yu, Yang; Zhong, Chongli; Lang, Qi; Liang, Zhiyun; Li, Yang; Shi, Yu; Jian, Jian; Xu, Feng; Tian, Yu

doi:10.3892/ijo.2022.5402

Cited by 10 publications

(14 citation statements)

References 54 publications

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“…Expression of EMT markers, such as E-cadherin, N-cadherin, and Vimentin, were significantly changed after the knockdown of HHLA2 expression in human ccRCC [ 27 ]. Zhang et al found out that HHLA2 via an impact on EMT in advanced gallbladder cancer can promote tumor progression [ 28 ]. They presented the hypothesis that HHLA2 may be involved in the Wnt/βcatenin axis.…”

Section: Discussionmentioning

confidence: 99%

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

Kula

Dawidowicz

Mielcarska

et al. 2023

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

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

Kula

Dawidowicz

Mielcarska

et al. 2023

IJMS

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“…Studies show that HHLA2 could play a significant role in gallbladder cancer (GBC) as well. Zhang et al found that among 89 examined patients, all cases exhibited HHLA2 staining [36]. In another study, high HHLA2 expression was observed in 53.68% of samples in the training group and 60.19% of cases in the testing group.…”

Section: Hhla2 In Gallbladder Cancermentioning

confidence: 93%

“…Notably, according to other authors, higher Nevin and TNM stages were associated with the high expression of HHLA2, B7-H3, and B7-H4 in both the training and testing groups. Elevated HHLA2 expression was also correlated with a lower density of CD8+ TILs in the training group (p = 0.001), but there was no relationship between HHLA2 expression and Foxp3 + TILs [36,37].…”

Section: Hhla2 In Gallbladder Cancermentioning

confidence: 95%

“…B7-H3 and HHLA2 were expressed together in 43.16% and 48.54% of samples, while B7-H4 was co-expressed with HHLA2 in 37.89% and 43.69% of cases in the training and the testing groups, respectively. These co-expression patterns could influence the effects of HHLA2 targeting in immunotherapies, therefore it is important to be mindful of this data [36,37]. Moreover, HHLA2 expression in GBC was more prominent than PD-L1 expression, suggesting that it could be a better therapeutic target in gallbladder cancer than PD-L1 [79].…”

Section: Hhla2 In Gallbladder Cancermentioning

confidence: 99%

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The Importance of HHLA2 in Solid Tumors—A Review of the Literature

Kula,

Koszewska,

Kot

et al. 2024

Cells

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Cancer immunotherapy is a rapidly developing field of medicine that aims to use the host’s immune mechanisms to inhibit and eliminate cancer cells. Antibodies targeting CTLA-4, PD-1, and its ligand PD-L1 are used in various cancer therapies. However, the most thoroughly researched pathway targeting PD-1/PD-L1 has many limitations, and multiple malignancies resist its effects. Human endogenous retrovirus-H Long repeat-associating 2 (HHLA2, known as B7H5/B7H7/B7y) is the youngest known molecule from the B7 family. HHLA2/TMIGD2/KIRD3DL3 is one of the critical pathways in modulating the immune response. Recent studies have demonstrated that HHLA2 has a double effect in modulating the immune system. The connection of HHLA2 with TMIGD2 induces T cell growth and cytokine production via an AKT-dependent signaling cascade. On the other hand, the binding of HHLA2 and KIR3DL3 leads to the inhibition of T cells and mediates tumor resistance against NK cells. This review aimed to summarize novel information about HHLA2, focusing on immunological mechanisms and clinical features of the HHLA2/KIR3DL3/TMIGD2 pathway in the context of potential strategies for malignancy treatment.

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“…[173][174][175][176] In in vivo experiments of human gallbladder cancer, the HHLA2 overexpression promoted tumor progression while its knockdown reduced the sizes of the GBC tumors. 177 Conversely, the HHLA2 ablation inhibited both TGF-β1-and long noncoding RNA H19-induced GBC progression in vitro. However, in a recent study on human ccRCC that evaluated the HHLA2 prognostic value, a positive correlation between increased HHLA2 and survival rates is reported.…”

Section: New B7 Family Checkpoints Moleculesmentioning

confidence: 98%

Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands

Kamali,

Bautista,

Eisenhut

et al. 2023

Therapeutic Advances in Vaccines and Immunotherapy

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Checkpoint markers and immune checkpoint inhibitors have been increasingly identified and developed as potential immunotherapeutic targets in various human cancers. Despite valuable efforts to discover novel immune checkpoints and their ligands, the precise roles of their therapeutic functions, as well as the broad identification of their counterpart receptors, remain to be addressed. In this context, it has been suggested that various putative checkpoint receptors can be induced upon activation. In the tumor microenvironment, T cells, as crucial immune response against malignant diseases as well as other immune central effector cells, such as natural killer cells, are regulated via co-stimulatory or co-inhibitory signals from immune or tumor cells. Studies have shown that exposure of T cells to tumor antigens upregulates the expression of inhibitory checkpoint receptors, leading to T-cell dysfunction or exhaustion. Although targeting immune checkpoint regulators has shown relative clinical efficacy in some tumor types, most trials in the field of cancer immunotherapies have revealed unsatisfactory results due to de novo or adaptive resistance in cancer patients. To overcome these obstacles, combinational therapies with newly discovered inhibitory molecules or combined blockage of several checkpoints provide a rationale for further research. Moreover, precise identification of their receptors counterparts at crucial checkpoints is likely to promise effective therapies. In this review, we examine the prospects for the application of newly emerging checkpoints, such as T-cell immunoglobulin and mucin domain 3, lymphocyte activation gene-3, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), new B7 family proteins, and B- and T-cell lymphocyte attenuator, in association with immunotherapy of malignancies. In addition, their clinical and biological significance is discussed, including their expression in various human cancers, along with their roles in T-cell-mediated immune responses.

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HHLA2 promotes tumor progression by long non‑coding RNA H19 in human gallbladder cancer

Cited by 10 publications

References 54 publications

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

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

The Importance of HHLA2 in Solid Tumors—A Review of the Literature

Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands

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