Abstract
Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells.
Highlights
Esophageal cancer is one of the most common cancers worldwide, with higher incidence rates in Eastern Asia and in Eastern and Southern Africa, in which esophageal squamous cell carcinoma (ESCC) accounts for the predominant histological type [1]
We found no angiogenic ability of Human umbilical vein endothelial cells (HUVECs) in the absence of B cells (Fig. 6b), suggesting that high-mobility group box 1 (HMGB1) derived from ESCC cells alone was not sufficient to elicit tumor angiogenesis in vitro
The results showed that the average sprout length in HUVECs treated with conditioned medium (CM) from co-culturing B cells with HMGB1-overexpressing tumor cells at 72 h was significantly longer (3.716 ± 5.062 μm/spheroid) than in those treated with control medium (1.692 ± 2.535 μm/spheroid)
Summary
Esophageal cancer is one of the most common cancers worldwide, with higher incidence rates in Eastern Asia and in Eastern and Southern Africa, in which esophageal squamous cell carcinoma (ESCC) accounts for the predominant histological type [1]. Tumor vasculature and stromal components within the TME may pose a barrier against intratumoral trafficking of C D8+ T cells [5, 6]; T cell therapies are modestly efficacious and patients often develop resistance. For this reason, additional therapeutic interventions are required for non-T cell-inflamed tumors to appropriately remodel the TME to render these tumors more sensitive to cancer treatments [7]. Regarding ESCC, it has been reported that HMGB1 was overexpressed in the tumor and plasma of Based on these data, we designed a study aimed at identifying the role of cancer-derived HMGB1 in the immune contexture of the TME, with particular focus on B cells, which could potentiate the tumorigenicity of ESCC through angiogenesis
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