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Among 167 CRC patients, HHLA2 expression was assessed by immunohistochemistry and ELISA, and HHLA2 upregulation was linked to cancer-related pathways. 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Dawidowicz, M.; Mielcarska, S.; Kiczmer, P.; Skiba, H.; Krygier, M.; Chraba ´nska, M.; Piecuch, J.; Szrot, M.; Robotycka, J.; et al. Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer. Int. J. Mol. Sci. 2023, 24, 5876. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms24065876](10.3390/ijms24065876)  \nAcademic Editor: Valentina De Falco  \nReceived: 10 February 2023  \nRevised: 12 March 2023  \nAccepted: 16 March 2023  \nPublished: 20 March 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland  \n2 Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland  \n3 Department and Chair of Pathomorphology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 13-15 3 Maja, 41-800 Zabrze, Poland  \n4 Department of General and Bariatric Surgery and Emergency Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland  \n5 Department of Microbiology and Immunology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland  \n* Correspondence: [d201070@365.sum.edu.pl](d201070@365.sum.edu.pl)  \nAbstract: 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. Fur","cbCaicC0YiyIXJRq","https://ap.wps.com/l/cbCaicC0YiyIXJRq","pdf",4794900,21,"English","# Abstract\n## Background and rationale\n## Methods overview\n## Results highlights","[{\"question\":\"What was the main purpose of the study on HHLA2 in colorectal cancer?\",\"answer\":\"To investigate correlations between HHLA2 levels and clinical, immune, histopathological, and signaling parameters in colorectal cancer.\"},{\"question\":\"How was HHLA2 expression measured in the study?\",\"answer\":\"HHLA2 expression was detected using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) in 167 colorectal cancer patients.\"},{\"question\":\"What key relationships did the study report regarding HHLA2?\",\"answer\":\"High HHLA2 expression was found in CRC tumor tissues versus adjacent noncancerous tissues, and HHLA2 upregulation correlated with cancer-related pathways; moreover, TIL score positively related to IHC HHLA2 expression percentage.\"}]","Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer | PDF",1790226766,53]