Oxygen-carrying nanoemulsions and respiratory hyperoxia eliminate tumor hypoxia–induced immunosuppression
Katarina Halpin-Veszeleiova, Michael P. Mallouh, Lucy M. Williamson, Ashley C. Apro, Nuria R. Botticello-Romero, Camille Bahr, Maureen Shin, Kelly M. Ward, Laura Rosenberg, Vladimir B. Ritov, Michail V. Sitkovsky, Edwin K. Jackson, Bruce D. Spiess, Stephen M. Hatfield
Katarina Halpin-Veszeleiova, Michael P. Mallouh, Lucy M. Williamson, Ashley C. Apro, Nuria R. Botticello-Romero, Camille Bahr, Maureen Shin, Kelly M. Ward, Laura Rosenberg, Vladimir B. Ritov, Michail V. Sitkovsky, Edwin K. Jackson, Bruce D. Spiess, Stephen M. Hatfield
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Research Article Immunology Oncology

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

Abstract

Hypoxia/hypoxia-inducible factor 1α–driven immunosuppressive transcription and cAMP-elevating signaling through A2A adenosine receptors (A2ARs) represent a major tumor-protecting pathway that enables immune evasion. Recent promising clinical outcomes due to the blockade of the adenosine-generating enzyme CD73 and A2AR in patients refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). We show that oxygenation agent therapy (a) eliminates tumor hypoxia, (b) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby (c) promotes regression of tumors in different anatomical locations. We show that both T cells and NK cells avoid hypoxic tumor areas and that reversal of hypoxia by oxygenation agent therapy increases intratumoral infiltration of activated T cells and NK cells due to reprogramming of the tumor microenvironment (TME). Thus, repurposing oxygenation agents in combination with supplemental oxygen may improve current cancer immunotherapies by preventing hypoxia-adenosinergic suppression, promoting immune cell infiltration and enhancing effector responses. These data also suggest that pretreating patients with oxygenation agent therapy may reprogram the TME from immunosuppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy.

Authors

Katarina Halpin-Veszeleiova, Michael P. Mallouh, Lucy M. Williamson, Ashley C. Apro, Nuria R. Botticello-Romero, Camille Bahr, Maureen Shin, Kelly M. Ward, Laura Rosenberg, Vladimir B. Ritov, Michail V. Sitkovsky, Edwin K. Jackson, Bruce D. Spiess, Stephen M. Hatfield

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Figure 5

Oxygenation agent therapy improves efficacy of adoptive T cell therapy.

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Oxygenation agent therapy improves efficacy of adoptive T cell therapy. ...
Mice with 11-day-established pulmonary metastases received ACT of 10 × 106 T cells. One day prior to ACT, mice underwent lymphodepletion with 100 mg/kg i.p. cyclophosphamide to mimic clinical protocols. Several hours prior to ACT, mice received i.v. administration of 10 mL/kg of PFC followed by 5 additional doses on days 12, 13, 14, 17, and 19. On day 11 (same day as ACT), mice were placed in a 60% O2 chamber to maximize PFC O2 transport or maintained at 21% O2 as control until assay completion on day 21. After termination of the study, mice were sacrificed, and lung tumors enumerated by counterstaining with India ink. (A) Images of tumor-bearing lungs from control versus PFC + 60% O2 + ACT (white arrows indicate metastatic nodules on the lungs prior to counterstaining). (B) Quantification of the number of metastatic nodules. Lungs with more than 250 tumors were denoted as such since this is the maximum number that can be counted reliably. P values were calculated using 1-way ANOVA with post hoc Tukey’s HSD. **P < 0.005; ***P < 0.0005. Data are presented as mean ± SEM, n ≥ 9.