The Novel HDAC Inhibitor OBP-801 Promotes MHC Class I Presentation Through LMP2 Upregulation, Enhancing the PD-1-Targeting Therapy in Clear Cell Renal Cell Carcinoma.

Simple Summary: Immune checkpoint inhibitors are used in combination with other drugs as the first-line therapy in the treatment of metastatic renal cell carcinoma. Although these cancer immunotherapies have demonstrated high therapeutic efficacy, half of patients develop treatment resistance. In this study, we investigated the enhancement of the antitumor effect of immunosuppressants by a histone deacetylase (HDAC) inhibitor. A novel HDAC inhibitor, OBP-801, upregulated LMP2, an immunoproteasome subunit, in clear cell renal cell carcinoma (ccRCC) cells, resulting in enhanced MHC class I expression, and a combined treatment of OBP-801 and anti-PD-1 antibody effectively alleviated ccRCC in mice. Our results suggest that manipulating LMP2 expression using OBP-801 may have therapeutic implications for enhancing MHC class I presentation and improving the anti-tumor immune response in ccRCC. In particular, the combination of OBP-801 with anti-PD-1 antibody appears to be promising for ccRCC treatment. Background: Histone deacetylase (HDAC) inhibitors have been reported to exhibit immunomodulatory activities, including the upregulation of major histocompatibility complex class I (MHC class I). Although the immunoproteasome plays a pivotal role in MHC class I antigen presentation, its effect on immunotherapy for clear cell renal cell carcinoma (ccRCC) remains unclear. Methods: This study assessed whether OBP-801, a novel HDAC inhibitor, affects the expression of immunoproteasome subunits and subsequently the MHC class-I-mediated anti-cancer immunity in ccRCC. We analyzed the data of 531 patients with ccRCC from the Cancer Genome Atlas Kidney Clear Cell Carcinoma database. We further evaluated the treatment efficacy of the combination of OBP-801 and anti-PD-1 in a ccRCC mouse model. Results: Low molecular mass polypeptide (LMP) 2 was correlated most positively with CD3E, CD8A, and CD8B expression and estimated CD8+ T cell number. In vitro studies showed that OBP-801 upregulated MHC class I presentation by inducing LMP2 expression in the ccRCC cell lines RENCA, 786-O, and Caki-1. In vivo studies in a syngeneic mouse model with subcutaneous implantation of RENCA cells showed that OBP-801 treatment increased the percentage of CD45+CD3e+ T cells in tumor-infiltrating lymphocytes. The combination of anti-PD-1 antibody and OBP-801 enhanced the anti-tumor effect, LMP2 protein expression, and MHC class I presentation in tumor cells. MHC class I presentation in the tumors of each mouse was positively correlated with the percentage of CD45+CD3e+ T cells. Conclusions: Our results demonstrate that OBP-801 promotes MHC class I presentation through LMP2 upregulation in tumor cells and thereby potentiates PD-1-targeting therapy. These data suggest that the combination of OBP-801 and anti-PD-1 treatment is a promising therapeutic strategy for ccRCC. [ABSTRACT FROM AUTHOR]