Mechanisms of Hypoxia-Mediated Immune Escape in Cancer

Abstract

An important aspect of malignant progression is the acquired ability of tumor cells to avoid recognition and destruction by the immune system (immune escape). Clinical cancer progression is also associated with the development of tumor hypoxia, which is mechanistically linked to the acquisition of malignant phenotypes in cancer cells. Despite the well-established role of hypoxia in tumor cell invasion and metastasis, and resistance to therapy, relatively few studies have examined the contribution of hypoxia to cancer immune escape. Accumulating evidence reveals that hypoxia can impair anticancer immunity by altering the function of innate and adaptive immune cells and/or by increasing the intrinsic resistance of tumor cells to the cytolytic activity of immune effectors. Here, we discuss certain aspects of the contribution of hypoxia to tumor immune escape and provide evidence for a novel role of cyclic guanosine monophosphate (cGMP) signaling in the regulation of hypoxia-induced immune escape. Thus, we propose that activation of cGMP signaling in cancer cells may have important immunotherapeutic applications. Cancer Res; 74(24); 7185-90. Ó2014 AACR.

The impact of hypoxia on tumor-associated macrophages

“…A self-sustaining capacity of the tumor microenvironment also includes immune regulatory function, as suppression of the immune cell executer function and evasion of the immune response play a pivotal role in tumor progression (41). Hypoxia is intertwined in this response, as it contributes to a general shift from an antitumoral Th1-type response to a protumoral Th2-type response.…”

From mice to humans: developments in cancer immunoediting

“…Notably, high levels of VEGF were also shown to negate the positive influence of infiltrating Th1/CD8 + T cells in ovarian and colorectal cancer (108,109). In addition, evidence is now emerging that links hypoxia-induced angiogenesis with immune tolerance (110). Altered glucose metabolism (an emerging hallmark of cancer) (2) and acidification have also been linked with denaturation of IFN-γ and suppression of TNF production (111).…”

The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation

“…On the other hand, unavoidable hypoxia in TME can be fertile ground for generation of regulatory immune cells, such as regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) in tumor [31]. Importantly, HIF-1 is pertinent factor involved in regulation of metabolic commitment of immune cells, immunometabolism, thus controlling their activation, proliferation, and effector functions [32].…”