Abstract
Despite the widespread use of the blockade of immune checkpoints, for a significant number of cancer patients, these therapies have proven ineffective, presumably due to the immunosuppressive nature of the tumor microenvironment (TME). Critical drivers of immune escape in the TME include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which not only mediate immune suppression, but also facilitate metastatic dissemination and impart resistance to immunotherapies. Thus, strategies that convert them into tumor fighters may offer great therapeutic potential. In this study, we evaluated whether pharmacologic modulation of macrophage phenotype by HDAC inhibitors (HDACi) could produce an anti-tumor effect. We demonstrated that low-dose HDACi trichostatin-A (TSA) markedly reshaped the tumor immune microenvironment by modulating the suppressive activity of infiltrating macrophages and inhibiting the recruitment of MDSCs in various tumors. These actions, in turn, augmented anti-tumor immune responses and further enhanced anti-tumor effects of immunotherapies. HDAC inhibition, however, also upregulated PD-L1, thereby limiting the beneficial therapeutic effects. Indeed, combining low-dose TSA with anti-PD-L1 in this model significantly enhanced the durability of tumor reduction and prolonged survival of tumor-bearing mice, compared with the effect of either treatment alone. These data introduce HDAC inhibition as a potential means to harness the anti-tumor potential of macrophages in cancer therapy.
Highlights
The success of checkpoint immunotherapy has created optimism that cancer may be curable
We demonstrate that histone deacetylases (HDAC) inhibition decreases the trafficking of myeloid-derived suppressor cells (MDSCs) into tumors, and potentiates tumor-associated macrophages (TAMs) to specify anti-tumoral phenotype and bolster T cells activation within the tumor microenvironment (TME)
Growing evidence demonstrates that HDACs are overexpressed in a variety of primary human tumors [25], including breast cancer, and we found that higher levels of specific HDACs are associated with a significantly poorer outcome in patients with either breast cancer (Supplementary Fig. 1a) or lung cancer (Supplementary Fig. 1b), justifying the potential use of HDAC inhibitors (HDACi) in cancer therapy
Summary
The success of checkpoint immunotherapy has created optimism that cancer may be curable. HDAC inhibition potentiates anti-tumor activity of macrophages and enhances anti-PD-L1-mediated tumor. Concerning, as widely used antibody-based therapeutics require substantial phagocytic activity of macrophages to induce antibody-dependent cell cytotoxicity/phagocytosis (ADCC/ADCP) [13, 14]. Macrophages have been shown to be required for the efficacy of cancer immunotherapy [15], depleting TAMs during cancer therapy may undermine immunotherapy. Attempts have been made to repolarize macrophage phenotypes, instead of depleting them [8, 9]. A better understanding of mechanisms governing TAMs phenotypic changes and functional responses is fundamental to the development of cancer immunotherapies targeting macrophages
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