1,5-AG suppresses pro-inflammatory polarization of macrophages and promotes the survival of B-ALL in vitro by upregulating CXCL14

Cancer metabolic reprogramming is essential for tumor initiation and progression, and the role of tumor metabolites has been the focal point of recent cancer research (Martinez-Reyes and Chandel, 2021). The tumor microenvironment (TME) is an intricate dynamic niche with many interacting cell types and extracellular components to form a unique physiology in which abnormal metabolites are repurposed to support neoplasm metabolism and growth (Lyssiotis and Kimmelman, 2017, Nallasamy et al., 2022). Tumor-associated macrophages (TAMs) are the most abundant innate immune population within the TME (Christofides et al., 2022, Robinson et al., 2021). Metabolites in the TME could reprogram immune cells, consequently affecting tumor immunological effects. The absence of TAM-mediated immune responses results in immune suppression due to the direct exchange of metabolites or through cytokines and other signaling mediators (Chen et al., 2021). Therefore, further research on regulating metabolites/intermediates on tumors and TME is imperative to improve therapeutics.

Macrophages are essential innate immune cells and can regulate various downstream signaling pathways of miscellaneous immune cells in the TME (Woo et al., 2015). Additionally, macrophages are highly plastic cells with multiple functions, including phagocytosis, exogenous antigen presentation, and immunomodulation (Boutilier and Elsawa, 2021, Varol et al., 2015). Over the last two decades, a conceptual framework for describing macrophage activation has been developed, which represents the two polar extremes of signals based on the surface molecules, secreted cytokine, and metabolic signatures (Xue et al., 2014, Zhang et al., 2021). Macrophages are primarily divided into classically activated pro-inflammatory M1 macrophages and alternatively activated anti-inflammatory M2 macrophages (Gordon, 2003, Murray, 2017). Metabolism governs macrophages' differentiation, polarization, mobilization, and ability to mount an effective anti-tumor response (Mehla and Singh, 2019). Macrophages can infiltrate into the TME via chemokines, including the chemokine ligand (CCL)2, CCL5, C-X-C chemokine ligand (CXCL) 12, and vascular endothelial growth factor (Christofides et al., 2022). Once recruited to the tumor site, the TAMs can be remodeled into immunosuppressive and tumor-promoting phenotypes by various tumor cell or stromal cell-derived factors, consequently leading to angiogenesis, tumorigenesis, TME remodeling, metastasis, immunosuppression, recurrence, and drug resistance (Cassetta et al., 2019, Komohara et al., 2014; Li et al., 2020). Therefore, abnormal metabolites such as adenosine (Wang et al., 2021), lactic acid (Colegio et al., 2014), and glutamine (Li et al., 2022) can drive macrophage plasticity and polarization (Mehla and Singh, 2019), fostering a tumor-permissive milieu.

B-lineage acute lymphoblastic leukemia (B-ALL) is a clonal hematopoietic neoplasm and one of the most common malignant childhood cancers. Despite the 90 % complete remission rate of existing therapeutic agents, drug resistance, recurrence, long-term adverse reactions, and unclear etiology and pathogenesis still pose considerable challenges in treating B-ALL(Inaba et al., 2013; Inaba and Mullighan, 2020; Jedraszek et al., 2022). B-ALL blasts reportedly remodel a vascularized microenvironment during disease initiation and chemotherapy, promoting monocytic differentiation. These non-classical monocytes may emerge to repair the damaged endothelium caused by leukemia-induced tissue inflammation (Witkowski et al., 2020). In hematologic malignancies, the TME can induce the activation of macrophages into M2 macrophages, which play a pivotal part in angiogenesis, immunosuppression, and tumor cells activation (Witkowski et al., 2020, Xie et al., 2022). Unfortunately, there is a paucity of extensive research on B-ALL-associated macrophages and metabolites in the B-ALL microenvironment. In addition, the mechanism of metabolites in regulating macrophage-dependent immune escape in B-ALL remains unclear.

Our previous studies (Zhu et al., 2023) identified an increase in the levels of the metabolite 1,5-anhydroglucitol (1,5-AG) in the plasma of patients with newly diagnosed B-ALL using untargeted metabolomics detection. 1,5-AG, a six-carbon monosaccharide structurally similar to glucose, is mainly obtained in food, absorbed, and reabsorbed by the intestine and renal tubules, respectively (Ying et al., 2018). Moreover, 1,5-AG is associated with diabetes mellitus, as evidenced by the significantly lower serum 1,5-AG level in patients with diabetes (Jimenez-Sanchez et al., 2022). Additionally, a related study demonstrated that 1,5-AG attenuates cytokine release from macrophages and suppresses inflammatory reactions in mice with type 2 diabetes (Meng et al., 2010). However, the role of 1,5-AG in tumors, particularly leukemia, has not yet been reported. Herein, we investigated the effects of 1,5-AG on macrophage polarization and determined that CXCL14 is the critical medium in this effect. Furthermore, we determined how macrophage polarization influences leukemia cell survival.

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