Checkpoint blockade immunotherapy has demonstrated significant clinical success in various malignant tumors. However, the therapeutic response is limited due to the immunosuppressive tumor microenvironment (ITM). In this study, a functional nanomaterial, layered double hydroxides (LDHs), carrying specific functional miR155 is developed to modulate ITM by synergistically repolarizing tumor associated macrophages (TAMs) to M1 subtype. LDH nanoparticles loaded with miR155 (LDH@155) exhibit superior ability in cellular uptake by murine macrophages, miR escape into the cytoplasm and TAMs specific delivery when introtumoral administration. Meanwhile, upon exposure to LDH@155, TAMs are significantly skewed to M1 subtype, which markedly inhibits myeloid‐derived suppressor cells (MDSCs) formation and stimulates T‐lymphocytes to secrete more interferon‐γ (IFN‐γ) cytokines in vitro. Introtumoral administration of LDH@155 reduces the percentage of TAMs and MDSCs in the tumor and elevates CD4 + and CD8 + T cell infiltration and activation, which can promote therapeutic efficiency of α‐PD‐1 antibody immunotherapy. Furthermore, it is found that LDH@155 significantly decreases the expression level of phosphorylated STAT3 and ERK1/2 and activates NF‐κB expression in TAMs, indicating that the STAT3, ERK1/2, and NF‐κB signaling pathways may involve in LDH@155‐induced macrophage polarization. Overall, the results suggest that LDH@155 nanoparticles may, in the future, function as a promising agent for cancer combinational immunotherapy.

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Background: CD73 is a cell surface enzyme which is highly expressed in the tumor microenvironment (TME). Degradation of adenosine monophosphate (AMP) into adenosine by CD73 results in the generation of an immunosuppressed and pro-angiogenic niche within the TME that promotes the onset and progression of cancer. Targeting CD73 has resulted in favourable anti-tumor effects in preclinical models and in clinic. One of the key mechanisms of therapeutic activity by CD73 inhibition is restoring the normal function of effector T cells from adenosine inhibition. ATG-037 is a highly potent and selective oral small molecule inhibitor of CD73. This study compared the ability of ATG-037 and clinical CD73 antibodies in reverting immunosuppression in higher-AMP environments in vitro. Methods: The activity of ATG-037 and CD73 antibodies (Hu101-28, MEDI9447) in inhibiting enzyme function of cell surface CD73 was evaluated by measuring the ATP-dependent oxidation of luciferin, which is inhibited by AMP, using Cell Titer Glo assay. Reversal of AMP/adenosine-mediated immune suppression of human T cells by CD73 inhibitors was determined by measuring T cell function in the presence of different concentrations of exogenous AMP. Markers for T cell proliferation, activation and cytotoxicity were assessed by flow cytometry, and the cytokine levels were measured by ELISA. Results: ATG-037, Hu101-28 and MEDI9447 inhibited the enzyme activity of cell surface-expressed CD73 on human A375 cells under 100 µM AMP with a half-maximal inhibitory concentration (IC50) of 0.36 nM,20.94 nM and 3.46 nM, respectively. ATG-037 demonstrated complete inhibition of CD73 activity, whereas MEDI9447 did not reach complete CD73 inhibition. T cell proliferation and activation induced by CD3/CD28 dynabeads were suppressed by 100 µM of extracellular AMP and the suppression was relieved by the addition of ATG-037 with half-maximal effective concentration (EC50) of 21.6 nM for CD8+ T cell proliferation, 27 nM for T cell activation, 2 nM for granzyme B expression, and 6.5 nM for T cell IFN-γ production. While Hu101-28 and MEDI9447 fail to restore the T cell function. In a mixed lymphocyte reaction assay, ATG-037, but not Hu101-28 or MEDI9447 reversed AMP-dependent T cell suppression. In addition, ATG-037 rescued immune cell activation in high AMP (500 µM, 1000 µM) environments. Conclusion: ATG-037 demonstrated potent and complete CD73 enzyme inhibition and stronger ability in restoring T cell function from high-level AMP mediated suppression, compared with clinical anti-CD73 antibodies. These data implicate the potential therapeutic advantages of small molecule CD73 inhibitors over blocking antibodies. Citation Format: Gang Bian, Jiahui Hua, Linjie Tian, Kevin Lynch, Jay Mei, Bo Shan, Bing Hou. ATG-037, a highly potent small molecule CD73 inhibitor has superior activity of reversing immunosuppression in higher-AMP environments compared with anti-CD73 antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2576.

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