Germinal center hypoxia in tumor-draining lymph nodes negatively regulates tumor-induced humoral immune responses in mouse models of breast cancer

Abstract

Hypoxia develops in germinal centers (GCs) induced by model antigens; however, it is unknown whether tumor-reactive GCs are also hypoxic. We identified GC hypoxia in lymph nodes (LNs) draining murine mammary tumors and lethally irradiated tumor cells, and found that hypoxia is associated with the levels of antibody-secreting B cells. Hypoxic culture conditions impaired the proliferation of activated B cells, and inhibited class-switching to IgG1 and IgA immunoglobulin isotypes in vitro . To assess the role of the hypoxic response in tumor-reactive GCs in vivo , we deleted von Hippel-Lindau factor (VHL) in class-switched B cells and found decreased GC B cells in tumor-draining LNs, reduced class-switched and tumor-specific antibodies in the circulation, and modified phenotypes of tumor-infiltrating T cells and macrophages. We also detected the hypoxia marker carbonic anhydrase IX in the GCs of LNs from breast cancer patients, providing evidence that GC hypoxia develops in humans. We conclude that GC hypoxia develops in TDLNs, and that the hypoxic response negatively regulates tumor-induced humoral immune responses in preclinical models.

Oxygen level is a critical regulator of human B cell differentiation and IgG class switch recombination

“…Variations in p O 2 are likely to affect the amplitude of B cell differentiation, due to profound effects of cellular metabolism as well as direct effects on transcriptional regulation ( 30 , 31 , 35 – 38 ). Although, contrasting findings have been reported for the influence of hypoxia on GC responses in mice, negative effects on class switch recombination and proliferation are repeatedly described ( 32 , 34 , 39 ). Others observed increased Tfh function induced by upregulation of HIF-1α, a major transcription factor involved in the cellular sensing of p O 2 ( 33 ).…”

Promise of hypoxia-targeted tracers in metastatic lymph node imaging

“…Hypoxic microenvironments result from aberrant tumor metabolism and dysregulated vascular supply; are associated with tumor progression, invasion, and metastasis; and lead to treatment failure in chemo-, radiation, and immunotherapies [6,7]. Locally advanced and recurrent cancers show enhanced hypoxia at the primary site as well as in the draining lymphatic nodes [6,8]. Traditional methods of hypoxia measurement rely on invasive polarographic methods in This article is part of the Topical Collection on Oncology -Head and Neck.…”