Heme oxygenase-1 orchestrates the immunosuppressive program of tumor-associated macrophages
Emmanuelle Alaluf, Benoît Vokaer, Aurélie Detavernier, Abdulkader Azouz, Marion Splittgerber, Alice Carrette, Louis Boon, Frédérick Libert, Miguel Soares, Alain Le Moine, Stanislas Goriely
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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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 4

Myeloid HO-1 controls antitumor T cell proliferation and cytotoxicity in the TME.

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Myeloid HO-1 controls antitumor T cell proliferation and cytotoxicity in...
An intravenous adoptive transfer of OT-1 cells (2 × 106 cells/mouse) was performed 10 days after tumor inoculation. This was followed by an immunization with subcutaneous injection of ovalbumin protein (50 μg/mouse) and poly(I:C) (50 μg/mouse) 1 hour later on the right flank of the animals. Two days later, EG7-OVA tumors were enzymatically and mechanistically digested and analyzed by flow cytometry. (A) Proportions of OT-1 cells in the spleen (n = 11 and n = 11), the draining lymph nodes (dLN) (n = 11 and n = 11) (axillary and inguinal lymph nodes on the right side), and the tumor (n = 24 and n = 23) of Hmox1ΔM mice compared with Hmox1fl/fl littermates. OT-1 cells were labeled with CFSE before intravenous adoptive transfer (2 × 106 cells/mouse). This was followed by an immunization of the mice as described above. (B) Tumor-infiltrating OT-1 cell proliferation assessed by CFSE dilution (n = 9 and n = 9) and (C) Ki-67 expression (n = 5 and n = 7) among OT-1 cells. (D) Granzyme B (GzmB) (n = 9 and n = 13) was analyzed by intracytoplasmic staining in tumor-infiltrating OT-1 cells. (E) Production of IFN-γ (n = 12 and n = 12) and MFI of (F) T-bet (n = 5 and n = 7) and (G) Eomes (n = 6 and n = 5) were assessed by ex vivo stimulation overnight with OVA SIINFEKL peptide (and brefeldin A added 2 hours later). Data are pooled from 3/4 experiments. Horizontal bars indicate median ± interquartile range. Statistical analysis was performed with Mann-Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.001.