Histone deacetylases (HDACs) are involved in diverse cellular regulatory mechanisms including non-canonical functions outside the chromatin environment. Several publications have demonstrated that selective HDAC inhibitors (HDACi) can influence tumor immunogenicity and the functional activity of specific immune cells. In particular, the selective inhibition of HDAC6 has been reported to decrease tumor growth in several malignancies. However, there is still no clarity about the cellular components mediating this effect. In this study, we evaluated the HDAC6i Nexturastat A as a priming agent to facilitate the transition of the tumor microenvironment from “cold” to “hot”, and potentially augment immune check-point blockade therapies. This combination modality demonstrated to significantly reduce tumor growth in syngeneic melanoma tumor models. Additionally, we observed a complete neutralization of the up-regulation of PD-L1 and other immunosuppressive pathways induced by the treatment with anti-PD-1 blockade. This combination also showed profound changes in the tumor microenvironment such as enhanced infiltration of immune cells, increased central and effector T cell memory, and a significant reduction of pro-tumorigenic M2 macrophages. The evaluation of individual components of the tumor microenvironment suggested that the in vivo anti-tumor activity of HDAC6i is mediated by its effect on tumor cells and tumor-associated macrophages, and not directly over T cells. Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically “cold” tumors and subsequently improve ongoing immune check-point blockade therapies.

Immune cells of the monocyte/macrophage lineage are characterized by their diversity, plasticity, and variety of functions. Among them, macrophages play a central role in antiviral responses, tissue repair, and fibrosis. Macrophages can be reprogrammed by environmental cues, thus changing their phenotype during an antiviral immune response as the viral infection progresses. While M1-like macrophages are essential for the initial inflammatory responses, M2-like macrophages are critical for tissue repair after pathogen clearance. Numerous reports have evaluated the detrimental effects that coronaviruses, e.g., HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2, have on the antiviral immune response and macrophage functions. In this review, we have addressed the breadth of macrophage phenotypes during the antiviral response and provided an overview of macrophage-coronavirus interactions. We also discussed therapeutic approaches to target macrophage-induced complications, currently under evaluation in clinical trials for coronavirus disease 2019 patients. Additionally, we have proposed alternative approaches that target macrophage recruitment, interferon signaling, cytokine storm, pulmonary fibrosis, and hypercoagulability.

Despite the outstanding clinical results of immune checkpoint blockade (ICB) in melanoma and other cancers, clinical trials in breast cancer have reported low responses to these therapies. Current efforts are now focused on improving the treatment efficacy of ICB in breast cancer using new combination designs such as molecularly targeted agents, including histone deacetylase inhibitors (HDACi). These epigenetic drugs have been widely described as potent cytotoxic agents for cancer cells. In this work, we report new noncanonical regulatory properties of ultra-selective HDAC6i over the expression and function of epithelial-mesenchymal transition pathways and the invasiveness potential of breast cancer. These unexplored roles position HDAC6i as attractive options to potentiate ongoing immunotherapeutic approaches. These new functional activities of HDAC6i involved regulation of the E-cadherin/STAT3 axis. Pretreatment of tumors with HDAC6i induced critical changes in the tumor microenvironment, resulting in improved effectiveness of ICB and preventing dissemination of cancer cells to secondary niches. Our results demonstrate for the first time that HDAC6i can both improve ICB antitumor immune responses and diminish the invasiveness of breast cancer with minimal cytotoxic effects, thus departing from the cytotoxicity-centric paradigm previously assigned to HDACi.Significance: Ultraselective HDAC6 inhibitors can reduce tumor growth and invasiveness of breast cancer by noncanonical mechanisms unrelated to the previously cytotoxic properties attributed to HDAC inhibitors.

Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma’s susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

No abstract

Histone deacetylases (HDACs) are involved in diverse cellular regulatory mechanisms including functions outside the chromatin environment. Several publications have demonstrated that selective HDAC inhibitors (HDACi) can influence tumor immunogenicity and the functional activity of specific immune cells. In particular, the selective inhibition of HDAC6 has been reported to decrease tumor growth in several malignancies. However, there is still no clarity about the cellular components mediating this effect. In this study, we evaluated the immunological modulation of the HDAC6i Nexturastat A in combination with anti-PD-1 checkpoint blockade therapy and the use of this HDAC6i as a priming agent to facilitate the transition of the tumor microenvironment from “cold” to “hot” in order to more specifically augment immune check-point blockade therapies. This combination of Nexturastat A and anti-PD-1 therapy demonstrated a significant reduction of tumor growth in syngeneic melanoma tumor animal models. Additionally, we observed a complete neutralization of the up-regulation of PD-L1 and other immunosuppressive pathways induced by the treatment with anti-PD-1 blockade. This combination also showed that the pre-treatment with selective HDAC6i induced major changes in the tumor microenvironment such as enhanced infiltration of immune cells, increased central and effector T cell memory, and a significant reduction of pro-tumorigenic M2 macrophages. The evaluation of the effect of HDAC6i on individual immune components suggest that the in vivo anti-tumor activity of HDAC6i is mediated by its effect on tumor cells and tumor associated macrophages, and not directly over T cells. Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically “cold” tumors and subsequently improve ongoing immune check-point blockade therapies. Note: This abstract was not presented at the meeting. Citation Format: Tessa J. Knox, Eva Sahakian, Debarati Banik, Melissa Hadley, Erica Palmer, Jennifer Kim, Satish Noonepalle, John Powers, Maria Gracia-Hernandez, Vasco Oliveira, Fengdong Cheng, Jie Chen, Cyril Barinka, Javier Pinilla-Ibarz, Norman Lee, Alan Kozikowski, Alejandro Villagra. Priming the tumor microenvironment with epigenetic modifiers to overcome resistance to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-074.

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