Hypoxia regulates vessel-modifying macrophages and vice versa in tumors

Abstract

Hypoxia, or low oxygen, is a common feature of solid tumors correlating with poor survival in cancer patients. Growing tumors need a blood supply to deliver oxygen. Tumors attempt to re-acquire oxygen by forming new blood vessels from nearby, pre-existing vessels, a process known as angiogenesis. Past treatments aimed at preventing this process yielded not only disappointing results in the clinic but sometimes worsened the patient’s prognosis making the tumor more hypoxic, emphasizing the urgent need for novel targets. In tumors, angiogenesis is notoriously dysfunctional resulting in leaky, under-perfused blood vessels which cannot adequately deliver oxygen and exacerbates hypoxia. Emerging treatments are now aimed at overcoming hypoxia by repairing tumor blood vessels and enhancing oxygen delivery to the tumor. Unfortunately, hypoxia causes immune suppression, preventing our bodies from eliminating cancer cells. One important immune cell affected by hypoxia is the macrophage. Normally, macrophages fight infections, activate killer T cells to eliminate cancer, and promote new blood vessel formation. However, tumor-associated macrophages (TAMs) suppress the proliferation and activity of killer T cells preventing them from eliminating cancer cells, and TAM overactivation leads dysfunctional angiogenesis that perpetuates the treatment-resistant, hypoxic tumor environment. In fact, increased number of TAMs reduces survival in solid tumor patients. Thus, molecular mechanisms in which macrophages respond to low oxygen tension has been increasingly investigated in the last decade as potential therapeutic targets. Hypoxia stabilizes hypoxia inducible transcription factors (HIF)-1α and HIF-2α in macrophages. Once thought to have overlapping roles, our understanding of their divergent functions is expanding. To investigate how hypoxia affects TAM function in breast tumors, we used mice in which breast cancer TAMs are deficient in HIF-1α or HIF-2α. We found that tumors with HIF-1α-deficient TAMs had 1) better blood vessel perfusion, 2) increased oxygenation, and 3) responded to chemotherapy unlike their wild type counterparts. Tumors with HIF-2α-deficient TAMs grew larger and despite having higher vessel density, had poor perfusion and oxygenation. This suggests HIF-1α in TAMs drives a pro-hypoxic phenotype that is suppressed by HIF-2α. Improved vessel function in these studies may also improve infiltration and proliferation of cancer-fighting killer T cells.