Hypoxia enhances IL-10-producing B cell generation through upregulating high-mobility group B1 on tumor cell-released autophagosomes

As common features of human solid tumors, hypoxia and nutrient starvation play multifaceted roles in cancer progress. However, the mechanisms are far from clear. Our previous work has indicated that tumor cell-released autophagosomes (TRAPs) are sufficient to suppress anti-tumor immune response in mouse by inducing IL-10-producing B cells through high-mobility group B1 (HMGB1). Here, we hypothesized that hypoxia or starvation might exert immunosuppressive effect through upregulating HMGB1 on TRAPs. We found that HMGB1 on TRAPs from human hepatocellular carcinoma cell line HepG2 played a significant role in IL-10-producing B cell induction. HMGB1 in tumor cells was upregulated under hypoxia and starvation, but only hypoxia significantly enhanced the level of HMGB1 present on the surfaces of TRAPs. Moreover, hypoxic TRAPs induced more IL-10-producing B cells with suppressive activities on CD4(+) and CD8(+) T cells. The finding indicates the role of TRAPs as a messenger of hypoxic response to enhance immunosuppression in tumor microenvironment.