Expression, clinical significance, and receptor identification of the newest B7 family member HHLA2 protein

Murali Janakiram, Jordan M. Chinai, Susan A. 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

Research output: Contribution to journalArticle

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Abstract

Purpose: HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 familymember 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 HHLA2protein expression innormalhuman tissues and cancers, as well as its prognostic significance, to explore mechanisms regulatingHHLA2 expression, and to identify candidateHHLA2 receptors. Experimental Design: An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors. Results: HHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I-III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2. Conclusions: Wide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy.

Original languageEnglish (US)
Pages (from-to)2359-2366
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number10
DOIs
StatePublished - May 15 2015

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Neoplasms
Proteins
Breast Neoplasms
Triple Negative Breast Neoplasms
T-Lymphocytes
Kidney
Tumor Microenvironment
Gene Dosage
Atlases
Immunosuppressive Agents
Gallbladder
Computational Biology
Placenta
Esophagus
Prostate
Pancreas
Ovary
Melanoma
Lung Neoplasms
Flow Cytometry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Expression, clinical significance, and receptor identification of the newest B7 family member HHLA2 protein. / Janakiram, Murali; Chinai, Jordan M.; Fineberg, Susan A.; Fiser, Andras; Montagna, Cristina; Medavarapu, Ramadevi; Castano, Ekaterina; Jeon, Hyungjun; Ohaegbulam, Kim C.; Zhao, Ruihua; Zhao, Aimin; Almo, Steven C.; Sparano, Joseph A.; Zang, Xingxing.

In: Clinical Cancer Research, Vol. 21, No. 10, 15.05.2015, p. 2359-2366.

Research output: Contribution to journalArticle

Janakiram, Murali ; Chinai, Jordan M. ; Fineberg, Susan A. ; Fiser, Andras ; Montagna, Cristina ; Medavarapu, Ramadevi ; Castano, Ekaterina ; Jeon, Hyungjun ; Ohaegbulam, Kim C. ; Zhao, Ruihua ; Zhao, Aimin ; Almo, Steven C. ; Sparano, Joseph A. ; Zang, Xingxing. / Expression, clinical significance, and receptor identification of the newest B7 family member HHLA2 protein. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 10. pp. 2359-2366.
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abstract = "Purpose: HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 familymember 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 HHLA2protein expression innormalhuman tissues and cancers, as well as its prognostic significance, to explore mechanisms regulatingHHLA2 expression, and to identify candidateHHLA2 receptors. Experimental Design: An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors. Results: HHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I-III triple-negative breast cancer, 56{\%} of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29{\%} of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2. Conclusions: Wide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy.",
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T1 - Expression, clinical significance, and receptor identification of the newest B7 family member HHLA2 protein

AU - Janakiram, Murali

AU - Chinai, Jordan M.

AU - Fineberg, Susan A.

AU - Fiser, Andras

AU - Montagna, Cristina

AU - Medavarapu, Ramadevi

AU - Castano, Ekaterina

AU - Jeon, Hyungjun

AU - Ohaegbulam, Kim C.

AU - Zhao, Ruihua

AU - Zhao, Aimin

AU - Almo, Steven C.

AU - Sparano, Joseph A.

AU - Zang, Xingxing

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Y1 - 2015/5/15

N2 - Purpose: HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 familymember 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 HHLA2protein expression innormalhuman tissues and cancers, as well as its prognostic significance, to explore mechanisms regulatingHHLA2 expression, and to identify candidateHHLA2 receptors. Experimental Design: An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors. Results: HHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I-III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2. Conclusions: Wide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy.

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