Oxygen-carrying nanoemulsions and respiratory hyperoxia eliminate tumor hypoxia-induced immunosuppression

Area of Science:

• Cancer immunology
• Tumor microenvironment
• Hypoxia research

Background:

• Hypoxia-inducible factor 1α (HIF-1α) drives immunosuppression and immune evasion via adenosine signaling through A2A adenosine receptors (A2ARs).
• Targeting CD73 and A2AR has shown clinical promise in refractory cancer patients, highlighting the significance of hypoxia-adenosinergic signaling in cancer progression.

Purpose of the Study:

• To investigate the feasibility of targeting upstream hypoxia-adenosinergic immunosuppression using oxygen-carrying nanoemulsions.
• To evaluate the impact of oxygenation agent therapy on tumor hypoxia, immune cell infiltration, and tumor regression.

Main Methods:

• Administration of an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute) to induce systemic oxygenation.
• Assessment of tumor hypoxia, T cell and NK cell infiltration, and tumor growth in preclinical models.
• Analysis of tumor microenvironment reprogramming in response to oxygenation therapy.

Main Results:

• Oxygenation agent therapy effectively eliminated tumor hypoxia.
• Therapy increased intratumoral infiltration and efficacy of both endogenous and adoptively transferred T cells and NK cells.
• Reversal of hypoxia reprogrammed the tumor microenvironment, promoting immune cell infiltration and leading to tumor regression across various anatomical locations.

Conclusions:

• Repurposing oxygenation agents, potentially with supplemental oxygen, can overcome hypoxia-adenosinergic immunosuppression in cancer.
• This strategy enhances immune cell infiltration and effector responses, offering a promising combination therapy to improve current cancer immunotherapies.
• Pretreatment with oxygenation agents may precondition the tumor microenvironment, making it more receptive to adoptive cell therapy and other immunotherapies.