Regulation of HHLA2 expression in kidney cancer and myeloid cells.

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-1ß 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.

Special type breast carcinoma: Sebaceous carcinoma of the breast; A case report and review of literature.

Sebaceous carcinoma of the breast is an extremely rare tumor. To the best of our knowledge only 15 cases have been reported in literature. Herein, we report a case of sebaceous carcinoma of the breast and describe the histopathologic features of sebaceous carcinoma of the breast in an elderly female.

The Role of the Pathologist in Renal Cell Carcinoma Management.

Recent advances in our understanding of the molecular alterations underlying different types of renal cell carcinoma (RCC), as well as the implementation of immune checkpoint inhibitors in the treatment of patients with advanced disease, have significantly expanded the role of pathologists in the management of RCC patients and in the identification of predictive biomarkers that can guide patient treatment. In this chapter, we examine pathologists' evolving role in patient care and the development of precision medicine strategies for RCC.

Colonic Carcinosarcoma: Report of a Rare Colorectal Malignancy and Review of Literature.

Colonic carcinosarcoma is an extremely rare tumor composed of mixed malignant epithelial and mesenchymal cells. Due to its rarity, its pathogenesis is poorly understood, and there are no specific guidelines for its treatment.