Immunological mechanisms of the antitumor effects of supplemental oxygenation

Abstract

Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors. This may limit further advances in cancer immunotherapy. There is a need for readily available and safe treatments that weaken the hypoxia–A2-adenosinergic immunosuppression in the TME. Recently, we reported that respiratory hyperoxia decreases intratumoral hypoxia and concentrations of extracellular adenosine. We show that it also reverses the hypoxia-adenosinergic immunosuppression in the TME. This, in turn, stimulates (i) enhanced intratumoral infiltration and reduced inhibition of endogenously developed or adoptively transfered tumor-reactive CD8 T cells, (ii) increased proinflammatory cytokines and decreased immunosuppressive molecules, such as transforming growth factor–β (TGF-β), (iii) weakened immunosuppression by regulatory T cells, and (iv) improved lung tumor regression and long-term survival in mice. Respiratory hyperoxia also promoted the regression of spontaneous metastasis from orthotopically grown breast tumors. These effects are entirely T cell– and natural killer cell–dependent, thereby justifying the testing of supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer.

CD73: A potential biomarker for anti-PD-1 therapy

“…Notably, our findings that A 2A blockade can enhance the activity of anti-PD-1 are supported by the recent study by Sitkovsky and colleagues who showed that the removal of the hypoxic (adenosine promoting) environment could enhance the activity of dual PD-1 and CTLA-4 blockade in an A 2A dependent manner. 7 Although our data supports a number of studies showing that blockade of the A 2A receptor enhances antitumor immunity, 3,[5][6][7] it has recently been observed that genetic ablation of A 2A can be deleterious in some tumor models due to reduced T cell effector memory differentiation/ survival. 8 Therefore, it may be that the pharmacodynamic and pharmacokinetic properties of A 2A antagonists are vital to their therapeutic outcome.…”

“…3 CD73 is an ectoenzyme which suppresses the antitumor immune response due to its conversion of AMP to adenosine which consequently suppresses immune responses due to the activation of A 2A and A 2B receptors on a wide range of immune cells including T lymphocytes. 5 Targeting this pathway by either direct inhibition of CD73 or the downstream A 2A /A 2B receptors has been shown to induce antitumor immunity 3,6,7 (and reviewed by Leone et al 5 ).…”

HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

“…CRT expression was induced by exposure of cardiomyocytes to hypoxia and reoxygenation (51), suggesting that the increased phagocytosis of NTC and DKD subclones after hypoxic exposure may be due to HIF-independent CRT expression, but further studies are required to test this hypothesis. A recent report demonstrated that CD47 blockade also promotes T-cell-mediated elimination of immunogenic tumors (52) and HIF-1 is known to inhibit effector T cells through the production of adenosine (23,47), suggesting that HIF inhibitors may improve the response to CD47 blockade both by inhibiting CD47 expression and by disinhibiting T-cell-mediated antitumor immunity.…”

“…Hypoxia induces the breast cancer stem cell (CSC) phenotype (19,20) through functional and physical interactions of HIF-1 with the coactivator TAZ (20,21) and by HIF-dependent expression of pluripotency factors (22). Hypoxia also induces immune evasion by several HIF-dependent mechanisms (23,24). A major mechanism by which cancer cells evade the innate immune system is by expression of CD47, which is a cell-surface protein that interacts with signal regulatory protein α (SIRPα) on the surface of macrophages to block phagocytosis (25,26).…”

Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

“…Adenosine binds to 4 known receptors: A 1 , A 2A (herein referred to as A 2A R), A 2B , and A 3 . Although A 2B and A 3 are also expressed on T cells, adenosine is thought to predominantly suppress endogenous antitumor T cell responses through stimulation of A 2A Rs expressed on activated T cells (18,23,24,(27)(28)(29)(30)(31). Indeed, A 2A Rdeficient mice (hereafter referred to as A 2A R -/-mice) are resistant to the immunosuppressive effects of adenosine and elicit enhanced antitumor immune responses (18,27,32,33).…”