Tumors may modulate host immunity partly through hypoxia-induced sympathetic bias

Hypoxia can occur in solid tumors when oxygen demand from rapid tumor growth outstrips the blood supply. Once thought to be merely a consequence of tumor physiology, more recent evidence suggests that hypoxia may also be a tumor adaptation to promote its own survival. For example, hypoxic conditions generate local transcriptional changes that enhance angiogenesis and glycolysis, processes that directly promote tumor growth. We hypothesize that maladaptive local chemoreceptor host response to hypoxia may contribute to a shift in immune balance that favors cancer survival. Specifically, we propose that hypoxia in the tumor microenvironment activates local adrenergic activity which in turn inhibits Th1 function while favoring Th2 function. Th1 function is vital to the host defense against cancer, and Th1 depletion is associated with increased cancer risk. In our view, the sympathetic bias induces Th2 bias independent of the direct immunomodulatory effects of tumor-derived cytokines. The hypoxia-induced local adrenergic response may be part of a broad tumor adaptation that enables its evasion of host immune surveillance. That the host response of Th2 bias is so reflexively linked to hypoxia may reflect the likelihood that trauma, rather than modern diseases such as cancer, were the most common causes of hypoxia during our teleologic past when natural selection shaped our biologic pathways. Validation of our hypothesis may shed more light on the biology of cancer and reveal novel diagnostic and therapeutic strategies.