Abstract 2168: Targeting HDAC6 to modulate the tumor microenvironment and enhance anti-PD-L1 immunotherapy in MSS colorectal cancer

Abstract Colon cancer is one of the most prevalent malignancies of the digestive system, characterized by high morbidity and mortality rates. Its development is driven by a complex interplay of factors within cancer cells and the tumor microenvironment (TME). Microsatellite-stable (MSS) colorectal cancer, often referred to as a “cold tumor, ” is characterized by chromosomal stability and a lack of neoantigen production. As a result, MSS tumors are generally unresponsive to immunotherapy. Post-translational modifications of proteins are critical in tumor remodeling and progression. Histone deacetylase 6 (HDAC6), a member of the HDAC family, plays a key role in regulating the deacetylation of both histone and non-histone substrates. Overexpression of HDAC6 has been reported in multiple tumor types and is associated with tumor growth and metastasis. While immune checkpoint blockade (ICB) therapies, such as those targeting programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1), have achieved clinical success in several malignancies, the majority of colorectal cancer patients particularly those with MSS tumors fail to respond to these treatments. Recent evidence indicates that the intratumoral immune context strongly influences the efficacy of ICB therapies. Patients with high levels of intratumoral CD8+ T cell infiltration, elevated tumor mutational burden (TMB), and increased PD-L1 expression within the TME are more likely to respond favorably to immunotherapy. In this study, we focused on enhancing the immunogenicity of the TME and upregulating PD-L1 expression through selective HDAC6 inhibition to improve the efficacy of anti-PD-L1 immunotherapy. Analysis of The Cancer Genome Atlas (TCGA) data revealed that HDAC6 expression is inversely correlated with several immune-related genes, including PD-L1. This inverse relationship suggests a potential role for HDAC6 in regulating immune responses in MSS colorectal cancer. These findings imply that HDAC6 may influence the TME and immune evasion mechanisms, particularly by modulating immune checkpoint molecules such as PD-L1. In the CT26 syngeneic mouse model, inhibition of HDAC6 led to an enhanced immune response characterized by increased PD-L1 expression, improved antigen presentation, and upregulation of MHC-II. This was accompanied by a polarization toward M1 macrophages and elevated levels of pro-inflammatory cytokines, including TNF-α and IFN-γ, which are crucial for T cell activation. Furthermore, HDAC6 inhibition resulted in a reduction of TGF-β, a key immunosuppressive cytokine, thereby moderating immune suppression within the tumor microenvironment. These results highlight the potential of HDAC6 inhibitors to reprogram the tumor immune landscape and sensitize MSS colorectal cancer to immune checkpoint therapies. Citation Format: Ahran Yu, Jeong Eun Kang, Ju Yeon Park, Seijong Kim, Hye Kyung Hong, Yong Beom Chov. Targeting HDAC6 to modulate the tumor microenvironment and enhance anti-PD-L1 immunotherapy in MSS colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2168.