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Published on: February 21, 2018
Regulation of HHLA2 expression in kidney cancer and myeloid cells
Tomonari Shigemura1, Nahuel Perrot2, Zimo Huang2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA, 02215, USA.
Background:
The immune checkpoint HERV-H LTR-associating 2 (HHLA2) is expressed in kidney cancer and various other tumor types. Therapeutics targeting HHLA2 or its inhibitory receptor KIR3DL3 are being developed for solid tumors, including renal cell carcinoma (RCC). However, the regulation of HHLA2 expression remains poorly understood. A better understanding of HHLA2 regulation in tumor cells and the tumor microenvironment is crucial for the successful translation of these therapeutic agents into clinical applications.
Methods:
Flow cytometry and quantitative real-time PCR were used to analyze HHLA2 expression in primary kidney tumors ex vivo and during in vitro culture. HHLA2 expression in A498 and 786-O ccRCC cell lines was examined in vitro and in subcutaneous tumor xenografts in NSG mice. Monocytes and dendritic cells were analyzed for HHLA2 expression. We tested a range of cytokines and culture conditions, including hypoxia, to induce HHLA2 expression.
Results:
Analysis of HHLA2 expression revealed that HHLA2 is expressed on tumor cells in primary kidney tumors ex vivo; however, its expression gradually diminishes during a 4-week in vitro culture period. A498 and 786-O ccRCC tumor cell lines do not express HHLA2 in vitro, but HHLA2 expression was observed when grown as subcutaneous xenografts in NSG immunodeficient mice. Induction experiments using various cytokines and culture conditions failed to induce HHLA2 expression in A498 and 786-O tumor cell lines in vitro. Analysis of HHLA2 expression in monocytes and dendritic cells demonstrated that only IL-10 and BMP4, along with IL-1β and IL-6 to a lesser extent, modestly enhanced HHLA2 protein and mRNA expression.
Conclusions:
HHLA2 expression is induced on kidney cancer cells in vivo by a tumor microenvironmental signal that is not present in vitro. HHLA2 expression is differentially regulated in kidney cancer epithelial cells and monocytes. Cytokines, particularly IL10, that induce HHLA2 expression in monocytes fail to upregulate HHLA2 expression in tumor cell lines in vitro. These findings underscore the importance of the interplay between tumor cell and tumor microenvironmental signals in the regulation of HHLA2. Further investigation is warranted to elucidate the mechanisms involved in HHLA2 regulation and its implications for therapeutic development.
Insights
Human endogenous retrovirus-H LTR-associating 2 (HHLA2) expression in kidney cancer is regulated by the tumor microenvironment. In vivo signals induce HHLA2 in kidney tumors, but not in vitro, highlighting the need for further research into therapeutic development.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The immune checkpoint HHLA2 (HERV-H LTR-associating 2) is present in kidney cancer and other tumors.
- Therapies targeting HHLA2 or KIR3DL3 are in development for solid tumors, including renal cell carcinoma (RCC).
- Understanding HHLA2 regulation in tumors and the microenvironment is vital for therapeutic success.
Purpose of the Study:
- To investigate the regulation of HHLA2 expression in kidney cancer.
- To explore the influence of the tumor microenvironment on HHLA2 expression.
- To understand differential HHLA2 regulation in tumor cells versus immune cells.
Main Methods:
- Flow cytometry and qRT-PCR analyzed HHLA2 expression in primary kidney tumors and cell lines (A498, 786-O).
- HHLA2 expression was studied in vitro, in vivo (xenografts in NSG mice), and in monocytes/dendritic cells.
- Cytokines, hypoxia, and culture conditions were tested for their ability to induce HHLA2 expression.
Main Results:
- HHLA2 was expressed in primary kidney tumors ex vivo but decreased in vitro.
- A498 and 786-O cells lacked HHLA2 in vitro but expressed it in vivo as xenografts.
- Cytokines (IL-10, BMP4, IL-1β, IL-6) modestly increased HHLA2 in monocytes/dendritic cells, but not in tumor cell lines in vitro.
Conclusions:
- Kidney cancer HHLA2 expression is induced in vivo by tumor microenvironmental signals absent in vitro.
- HHLA2 is regulated differently in kidney cancer epithelial cells and monocytes.
- Cytokines inducing HHLA2 in monocytes do not upregulate it in tumor cell lines, emphasizing tumor cell-microenvironment interplay.
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