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  • In this study we further expanded the

    2022-01-18

    In this study, we further expanded the antitumor bioactivity, with the BALB/c S-180 tumor model, which is long-established due to its highly aggressive in all strains of laboratory mice and rats (Cui et al., 2003). We investigated the tumor-regressing ability of β-glucan by different modes of administration, and established the connection between β-glucan and CD4+ T ISX 9 synthesis in tumor immune responses.
    Materials and methods
    Results and discussion
    Conclusion In summary, three β-glucans (AG, SG, and CG) from Lentinus edodes with different sources were isolated with the same chemical structure and different molecular weights. They all exhibited strong antitumor activity and the AG β-glucan with the highest antitumor bioactivity was chosen to investigate the mechanism of tumor-suppression in vivo. AG administrated orally, intraperitoneally or intratumorally all inhibited tumor-growth and targeted the tumor sites. AG up-regulated the CD4+ T cell level in lymphoid organs to reverse the impact of tumor burden, as well as in healthy mice. AG treatment altered the tumor microenvironment, promoted CD4+ T cell and neutrophil infiltration into tumor sites, drove neutrophils to the tumor site or directly recruits neutrophils from peripheral blood to kill tumors. This study thus offers a better understanding for treating cancer by oral β-glucans or a more effective way by intratumoral administration.
    Acknowledgement We gratefully acknowledge the financial supports from the National Natural Science Foundation of China (21574102, 21875167, and 21274114).
    Introduction Homeostasis is an essential period of the T cell lifespan during which various extrinsic signals are required to ensure T cell survival (Sprent et al., 2008, Surh and Sprent, 2008). In immunocompetent environments, naive T cells actively maintain quiescence as a means of avoiding overpopulation and loss due to neglect (Takada and Jameson, 2009). Alternatively, in lymphopenic hosts, naive T cells exhibit increased proliferative capacity as a means of reconstituting the host’s immune system. Because homeostasis requires a delicate balance between quiescence and proliferation, regulatory mechanisms are in place to safeguard against aberrant T cell responses. However, there remains a gap in our understanding as to how bioenergetics play a role in this process. In particular, lymphocyte activation gene-3 (LAG-3) has gained prominence as a key inhibitory receptor in various disease models (Delmastro et al., 2012, Jha et al., 2014). LAG-3 is structurally homologous to CD4 and possesses a greater affinity for their shared ligand, major histocompatibility complex (MHC) class II (Huard et al., 1997, Workman et al., 2002). Although the various inhibitory effects mediated by LAG-3, including dampening proliferation and Interferon γ (IFNγ) production (Workman et al., 2004, Workman and Vignali, 2003), have been characterized, its downstream signaling remains elusive. LAG-3 is also able to undergo proteolytic cleavage from the surface of cells via metalloprotease activity (Li et al., 2007), thereby alleviating its inhibitory effect. This additional level of post-translational regulation is unique to LAG-3, suggesting that LAG-3 serves as more of a modulator than an ultimate break. Naive CD4+ T cells express low levels of LAG-3 (Huang et al., 2004); nevertheless, LAG-3 engagement negatively regulates these cells. Studies examining global knockout (Workman and Vignali, 2005) and antibody blockade (Durham et al., 2014) indicated that homeostatic expansion is tightly regulated by LAG-3 in immunocompetent and lymphopenic animals. It is becoming more evident that cellular metabolic programs are essential for driving the identity and functionality of T cells. Unlike activated T cells, which demonstrate robust aerobic glycolysis to maximize macromolecule synthesis and energy, naive CD4+ T cells are considered metabolically quiescent (MacIver et al., 2013). Naive T cells rely predominantly on oxidative phosphorylation (OXPHOS) via mitochondria for generating ATP (Hua and Thompson, 2001). Signaling through the cytokine Interleukin-7 (IL-7) in naive T cells is essential for maintaining not only their survival, but also their metabolic profile (Jacobs et al., 2010, Wofford et al., 2008). IL-7 has been shown to increase glucose uptake in an Akt/signal transducer and activator of transcription 5 (STAT5)-dependent manner (Barata et al., 2004, Jacobs et al., 2010, Wofford et al., 2008). Alternatively, loss of CD127 (IL-7Rα) expression or antibody blockade disrupts naive T cell homeostasis, resulting in decreased proliferation and viability (Akashi et al., 1997, Gonzalez-Quintial et al., 2011).