Altering the tumor microenvironment and immune landscape through HDAC6 inhibition in melanoma
Open AccessSkin cancer is the most common form of cancer diagnosed in the United States (U.S.) every year [1] and is on the rise globally[2]. While there are multiple forms of skin cancer, melanoma is the deadliest form and accounts for nearly 75% of all skin cancer related deaths[3]. Over the last two decades, new cases of invasive melanoma have increased by 40% and effects individuals across all age groups[1]. Earlier stages of melanoma are typically successfully treated with surgical methods; however, more advanced stages of the disease have been notoriously difficult to treat. The advent of immunotherapy that harnesses the immune system of patients to fight cancer has revolutionized the way multiple tumor types are treated, including melanoma[4-7]. The use of immune checkpoint blockade (ICB) therapies such as nivolumab and pembrolizumab are two of the monoclonal antibodies that target the receptor known as programmed death 1 (PD-1). The PD-1 receptor is expressed in T cells and B cells, and its blockade has significantly improved the quality of life and overall survival (OS) in patients with melanoma[8]. Unfortunately, both innate and acquired resistance to ICB therapies remains a considerable hurdle in treating melanoma and other cancers. In order to overcome these challenges, considerable research has been dedicated to exploring combination therapies with small molecule inhibitors (SMIs) to improve upon the ICB therapies that are currently clinically available. Histone deacetylases (HDACs) are involved in various cellular regulatory mechanisms, including non-canonical functions outside the chromatin environment. These diverse biological roles include regulating the cell cycle[9], tumor suppression[10], angiogenesis[11], and immunomodulatory effects [12-14](i.e., altering the immune cell activity or cytokine production). While some HDAC inhibitors (HDACi) are clinically available, nonselective HDACi, that target multiple HDACs often have toxic side effects that limit their availability and use[15]. Our research has focused on using the highly selective HDAC6 inhibitor (HDAC6i) NextA in combination with anti-PD-1 therapy and in vivo mouse melanoma model. This work shows that a fully intact immune system is required for selective HDAC6i to impact tumor growth. In particular, we have found that treatment with HDAC6i leads to a decrease in the expression of inhibitory immunomodulatory ligands (i.e., PD-Ll) and immunosuppressive cytokines in the TME in vivo. In this same model, we found that HDAC6i leads to important shifts in the immune cell population found in tumors, enhanced infiltration of immune cells, increased central and effector T cell memory, and a significant reduction of pro-tumorigenic M2 macrophages. Further investigation using next-generation sequencing (NGS) methods revealed that treatment with NextA leads to changes in the expression of multiple chemokines, including CCL12. Further experiments using isolated murine bone marrow-derived macrophages (BMDM) demonstrate that the resulting alterations in this chemokine as a result of HDAC6i significantly impair the movement of M2 macrophages. Lastly, we found that multiple immunomodulatory ligands and antigen-presenting genes undergo changes in alternative splicing (AS) patterns when tumors are treated with NextA. Overall, the pharmacological and genetic abrogation of HDAC6 leads to major changes in the tumor microenvironment and immune landscape that we are only beginning to fully understand.
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