Abstract 6257: Developing HDAC inhibitors as immunomodulators

Abstract Immune checkpoint inhibitors (ICIs) are standard of care for several solid tumor types, including renal cell carcinoma (RCC). However, the clinical success of these therapies is dampened by the fact that the majority of patients demonstrate either inherent resistance to treatment or develop secondary resistance following an initial response. One key mechanism of tumor-driven ICI resistance is the generation and recruitment of suppressive immune cell types, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which coordinate to suppress anti-tumor T cell responses. Thus, there is a critical need for the development of novel combination strategies aimed at mitigating the presence and function of suppressive immune cells to improve the efficacy of ICIs in the clinic. Our laboratory has previously demonstrated that histone deacetylase inhibition (HDACi) is associated with a decrease in both the number and function of tumor-infiltrating Tregs and MDSCs in the RENCA tumor model. Thus, the overall goal of these studies both preclinically and clinically is to investigate the impact of the immunomodulatory effects of HDACi in combination with ICI therapy, with the overall hypothesis that HDACi will improve the efficacy of anti-PD1 therapy in RCC. Our pre-clinical data support this hypothesis by demonstrating increased tumor control and survival in RENCA tumor-bearing mice when treated with a combination of anti-PD1 and HDACi compared to single agent therapy. These increases were also associated with an increase in the activation state of anti-tumor immune cells, as demonstrated by increased surface expression of MHC Class II molecules on macrophages and a decrease in phenotypically defined monocytic MDSCs. ATACseq and RNAseq data generated from combination-treated animals also outline a gene expression signature associated with both myeloid and T cell activation. Interestingly, our clinical studies also afforded us the opportunity to investigate potential biomarkers associated with responder status, which will allow us to better predict patient outcomes and administer therapies accordingly. Accumulating evidence from two independent clinical trials run by our group suggests that high levels of suppressive CD11b+HLA-DRlo MDSCs at baseline in the peripheral blood is associated with lack of clinical response to the combination of HDACi and ICI. Overall, these data support the rationale for the combination of ICI and HDACi in the clinic, and provide a potentially useful biomarker through which we can predict the success of combination therapy. Citation Format: Sean Colligan, Li Shen, Christopher Rupert, Jonathan Bard, Roberto Pili. Developing HDAC inhibitors as immunomodulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6257.