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Masataka Shimonosono, Takaaki Arigami, Shigehiro Yanagita, Daisuke Matsushita, Yasuto Uchikado, Yuko Kijima, Hiroshi Kurahara, Yoshiaki Kita, Shinichiro Mori, Ken Sasaki, Itaru Omoto, Kosei Maemura, Yoshikazu Uenosono, Sumiya Ishigami, Shoji Natsugoe
Currently, immune checkpoint blockade against members of the B7/CD28 family is being used as a new molecular-targeted therapy, in patients with unresectable advanced or recurrent gastric cancer. Although human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a novel molecule of the B7/CD28 family, the clinical impact of its expression remains uncertain in gastric cancer. Consequently, we examined HHLA2 expression in blood specimens from patients with gastric cancer, and investigated the relationship between its expression and clinicopathological factors to assess its potential power as a prognostic blood predictor...
April 24, 2018: Oncotarget
Ziwen Zhu, Weiguo Dong
Background: Colorectal carcinoma (CRC) is one of the most common malignancies, and immunotherapy has opened a new field of cancer treatment in recent years. Generally, CRC does not benefit from immunotherapy. HHLA2, a member of the B7 family, is a novel immune checkpoint molecule, and the prognostic value of HHLA2 in CRC patients and the association between HHLA2 expression and clinicopathological characteristics remains unknown. Materials and methods: This study included 63 patients diagnosed with CRC, and their resected specimens were obtained and constructed as a tissue microarray...
2018: OncoTargets and Therapy
Haiying Cheng, Alain Borczuk, Murali Janakiram, Xiaoxin Ren, Juan Lin, Amer Assal, Balazs Halmos, Roman Perez-Soler, Xingxing Zang
Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non-small cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2. Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x, and HHLA2 on human T-cell proliferation and cytokine production were investigated...
April 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
M Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Carmen Molina, Saray Garasa, Arantza Azpilikueta, Iñaki Etxeberria, Alfonso R Sanchez-Paulete, Alan J Korman, Manel Esteller, Juan Sandoval, Ignacio Melero
CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA methylation arrays were carried out on human peripheral blood CD8+ T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors...
January 2018: Cancer Immunology Research
Alexander Sankin, Deepa Narasimhulu, Peter John, Benjamin Gartrell, Mark Schoenberg, Xingxing Zang
Over the last decade, a new understanding of tumor-immune system interplay has been ushered in, lead in large part by the discovery of immune checkpoints mediated through B7-CD28 family interactions. Therapeutic blockade of the PD-L1 immune checkpoint pathway has already shown great success as a cancer immunotherapy for advanced urothelial carcinoma, leading to durable clinical remissions in an otherwise incurable disease. There are newly described members of the B7-CD28 family including B7-H3, B7x, and HHLA2...
May 8, 2017: Urologic Oncology
Murali Janakiram, Urvi A Shah, Weifeng Liu, Aimin Zhao, Mark P Schoenberg, Xingxing Zang
The B7-CD28 family of ligands and receptors play important roles in T-cell co-stimulation and co-inhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules (B7-H3 [CD276], B7x [B7-H4/B7S1], and HHLA2 [B7H7/B7-H5]/TMIGD2 [IGPR-1/CD28H]) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7-H3, B7x, HHLA2, and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, transplantation, and infection...
March 2017: Immunological Reviews
Haiying Cheng, Murali Janakiram, Alain Borczuk, Juan Lin, Wanglong Qiu, Huijie Liu, Jordan M Chinai, Balazs Halmos, Roman Perez-Soler, Xingxing Zang
PURPOSE: Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC...
February 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Pratistha Koirala, Michael E Roth, Jonathan Gill, Jordan M Chinai, Michelle R Ewart, Sajida Piperdi, David S Geller, Bang H Hoang, Yekaterina V Fatakhova, Maya Ghorpade, Xingxing Zang, Richard Gorlick
Over the past four decades there have been minimal improvements in outcomes for patients with osteosarcoma. New targets and novel therapies are needed to improve outcomes for these patients. We sought to evaluate the prevalence and clinical significance of the newest immune checkpoint, HHLA2, in osteosarcoma. HHLA2 protein expression was evaluated in primary tumor specimens and metastatic disease using an osteosarcoma tumor microarray (TMA) (n = 62). The association of HHLA2 with the presence of tumor infiltrating lymphocytes (TILs) and five-year-event-free-survival were examined...
2016: Scientific Reports
Murali Janakiram, Vipul Pareek, Haiying Cheng, Deepa M Narasimhulu, Xingxing Zang
Tumor immune evasion is one of the hallmarks of cancer, and expression of the B7 family of immune checkpoints (PD-L1, PD-L2, B7-H3, B7x and HHLA2) is one mechanism of immune evasion by tumors to suppress T-cell function. Antibodies blocking these interactions of B7-1/B7-2/CTLA-4 and PD-L1/PD-L2/PD-1 have had remarkable clinical success in several cancers and are less toxic than traditional chemotherapy. Even though only a small proportion of patients respond to checkpoint blockade, the duration of such responders due to immunological memory is remarkable and is longer than would be expected with any other agent in refractory disease...
June 2016: Immunotherapy
Murali Janakiram, Jordan M Chinai, Aimin Zhao, Joseph A Sparano, Xingxing Zang
We and others recently discovered HHLA2 as a new B7 family member and transmembrane and immunoglobulin domain containing 2 (TMIGD2) as one of its receptors. Based on a new study we propose that HHLA2 may represent a novel immunosuppressive mechanism within the tumor microenvironment and hence could be a target for cancer therapy. TMIGD2 may be another therapeutic target.
August 2015: Oncoimmunology
Yanping Xiao, Gordon J Freeman
HHLA2 is a newly identified B7 family member that modulates T-cell functions through interaction with TMIGD2 and possibly a second receptor, with coinhibition in two studies and costimulation in one study. HHLA2 is expressed on a variety of human cancers, and its coinhibitory function makes it a candidate for cancer immunotherapy.
May 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Murali Janakiram, Jordan M Chinai, Susan Fineberg, Andras Fiser, Cristina Montagna, Ramadevi Medavarapu, Ekaterina Castano, Hyungjun Jeon, Kim C Ohaegbulam, Ruihua Zhao, Aimin Zhao, Steven C Almo, Joseph A Sparano, Xingxing Zang
PURPOSE: HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 family member that regulates human T-cell functions. However, its protein expression in human organs and significance in human diseases are unknown. The objective of this study was to analyze HHLA2 protein expression in normal human tissues and cancers, as well as its prognostic significance, to explore mechanisms regulating HHLA2 expression, and to identify candidate HHLA2 receptors. EXPERIMENTAL DESIGN: An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein...
May 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ruihua Zhao, Jordan M Chinai, Susan Buhl, Lisa Scandiuzzi, Anjana Ray, Hyungjun Jeon, Kim C Ohaegbulam, Kaya Ghosh, Aimin Zhao, Matthew D Scharff, Xingxing Zang
T-cell costimulation and coinhibition generated by engagement of the B7 family and their receptor CD28 family are of central importance in regulating the T-cell response, making these pathways very attractive therapeutic targets. Here we describe HERV-H LTR-associating protein 2 (HHLA2) as a member of the B7 family that shares 10-18% amino acid identity and 23-33% similarity to other human B7 proteins and phylogenetically forms a subfamily with B7x and B7-H3 within the family. HHLA2 is expressed in humans but not in mice, which is unique within the B7 and CD28 families...
June 11, 2013: Proceedings of the National Academy of Sciences of the United States of America
Martin F Flajnik, Tereza Tlapakova, Michael F Criscitiello, Vladimir Krylov, Yuko Ohta
The B7 family of genes is essential in the regulation of the adaptive immune system. Most B7 family members contain both variable (V)- and constant (C)-type domains of the immunoglobulin superfamily (IgSF). Through in silico screening of the Xenopus genome and subsequent phylogenetic analysis, we found novel genes belonging to the B7 family, one of which is the recently discovered B7H6. Humans and rats have a single B7H6 gene; however, many B7H6 genes were detected in a single large cluster in the Xenopus genome...
August 2012: Immunogenetics
D L Mager, D G Hunter, M Schertzer, J D Freeman
By screening the expressed sequence tag (EST) database, we identified transcripts of two new human genes that are polyadenylated within a long terminal repeat (LTR) of the HERV-H endogenous retrovirus family. The first gene, termed HHLA2, is represented by two EST clones and one cDNA clone, all of which have a polyadenylated LTR as their 3' end. The gene has an open reading frame (ORF) of 414 amino acids with three immunoglobulin-like domains and is expressed primarily in intestinal tissues, kidney, and lung...
August 1, 1999: Genomics
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