Heme oxygenase-1 orchestrates the immunosuppressive program of tumor-associated macrophages
Emmanuelle Alaluf, … , Alain Le Moine, Stanislas Goriely
Emmanuelle Alaluf, … , Alain Le Moine, Stanislas Goriely
Published June 4, 2020; First published May 5, 2020
Citation Information: JCI Insight. 2020;5(11):e133929. https://doi.org/10.1172/jci.insight.133929.
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Research Article Immunology Oncology

Heme oxygenase-1 orchestrates the immunosuppressive program of tumor-associated macrophages

Abstract

Tumor-associated macrophages (TAMs) contribute to the maintenance of a strong immunosuppressive environment, supporting tumor progression and resistance to treatment. To date, the mechanisms that drive acquisition of these immunosuppressive features are still poorly defined. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme that catabolizes free heme. It displays important cytoprotective, antiinflammatory, and antioxidant properties. A growing body of evidence suggests that HO-1 may also promote tumor development. Herein, we show that HO-1 is highly expressed in monocytic cells in the tumor microenvironment (TME) once they differentiate into TAMs. Deletion of HO-1 in the myeloid compartment enhances the beneficial effects of a therapeutic antitumor vaccine by restoring CD8+ T cell proliferation and cytotoxicity. We further show that induction of HO-1 plays a major role in monocyte education by tumor cells by modulating their transcriptional and epigenetic programs. These results identify HO-1 as a valuable therapeutic target to reprogram the TME and synergize with current cancer therapies to facilitate antitumor response.

Authors

Emmanuelle Alaluf, Benoît Vokaer, Aurélie Detavernier, Abdulkader Azouz, Marion Splittgerber, Alice Carrette, Louis Boon, Frédérick Libert, Miguel Soares, Alain Le Moine, Stanislas Goriely

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Figure 1

HO-1 expression is specifically induced by monocytic cells upon differentiation into macrophages in the TME.

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HO-1 expression is specifically induced by monocytic cells upon differen...
(A) HO-1 staining (in red) combined with DAPI costaining showing nuclei (in blue) visualized in tumor slices by immunofluorescence in F4/80+ myeloid cells (in green) in an EG7-OVA tumor 21 days after tumor inoculation in a WT mouse. Scale bar: 5 μm. (B) Flow cytometry plots pregated on live CD11b+ cells indicate 12 days after tumor inoculation the proportion of HO-1–producing cells among different tumor-infiltrating myeloid cell subtypes: the CD11bhiLy6G+ neutrophils (PMN), the CD11bhiLy6G–Ly6ChiMHCII– monocytes (I), the CD11bhiLy6G–Ly6ChiMHCII+ cells (II), and the CD11bhiLy6G–Ly6CloMHCII+ TAMs (III). Horizontal bars indicate median ± interquartile range (n = 6). (C) Representative histograms indicating by MFI the level of expression of the specified markers in HO-1+ (blue) versus HO-1– (red) TAMs. (D) Representative flow cytometry plots of the accumulation of immature myeloid cells compatible with myeloid-derived suppressor cell phenotype (CD11bhiLy6C+Ly6G– and CD11bhiLy6CintLy6G+ summarized as CD11b+Gr1+ cells) in the bone marrow (BM) and spleen from tumor-bearing WT mice. Data representative of 3 independent experiments. Each point represents an individual mouse. Horizontal bars indicate median ± interquartile range (E) HO-1 expression measured by flow cytometry among CD11b+Gr1+ cells from bone marrow, spleen, and EG7-OVA tumor from tumor-bearing WT mice, compared with tumor-free WT mice (naive). Horizontal bars indicate median ± interquartile; n = 3 (naive), and n = 6 (tumor-bearing group). Statistical analysis was performed with Mann-Whitney U test. ***P < 0.001; ****P < 0.0001.