Immunotherapy has revolutionized the treatment of certain cancers by facilitating the antitumor immune response and represents today one of the mainstays of cancer therapy. However, only a subset of patients responds to immunotherapy, which can also lead to serious complications. The tumor microenvironment is composed of multiple and complex cellular and molecular interactions providing to cancer cells not only a supportive framework but promoting also many steps of immunosuppression and tumor progression. To date, the mechanisms that drive the acquisition of these immunosuppressive features are still poorly defined. Tumor-associated macrophages can be highly represented in the tumor microenvironment where they are shaped and become key players in the innate and adaptive immune escape of the tumor cells.Heme oxygenase-1 is the rate-limiting enzyme that catabolizes heme into three major biologically active byproducts which display cytoprotective, antioxidant and immunomodulatory effects. We hypothesized that tumor-associated macrophages might suppress anti-tumor T-cell response through heme oxygenase-1 induction in the tumor microenvironment and macrophage polarization. We showed that heme oxygenase-1 is highly expressed in tumor-associated macrophages. By using a subcutaneous EG7-OVA lymphoma model on genetically engineered mice with a conditional deletion of heme oxygenase-1 in macrophages, our data show that myeloid-restricted heme oxygenase-1 deficiency improves the effect of a therapeutic antitumor immunization by enhancing tumor-infiltrating antitumor CD8+ T-cell proliferation and cytotoxicity and represses tumor growth. Our data suggest a major role of myeloid heme oxygenase-1 in the differentiation and the phenotypic, functional, transcriptional and epigenetic reprograming of tumor-associated macrophages. Myeloid HO-1 inhibition might be considered as a new myeloid HO-1-mediated immune checkpoint blockade. Targeting myeloid compartment could reprogram the tumor microenvironment and synergize with other cancer therapies. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished
| Identifer | oai:union.ndltd.org:ulb.ac.be/oai:dipot.ulb.ac.be:2013/312817 |
| Date | 29 September 2020 |
| Creators | Alaluf, Emmanuelle |
| Contributors | Le Moine, Alain, Corazza, F., De Wilde, Virginie, Detours, Vincent, Fuks, François, Libert, Claude, van der Bruggen, Pierre |
| Publisher | Universite Libre de Bruxelles, Université libre de Bruxelles, Faculté de Médecine – Médecine, Bruxelles |
| Source Sets | Université libre de Bruxelles |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:ulb-repo/semantics/doctoralThesis, info:ulb-repo/semantics/openurl/vlink-dissertation |
| Format | 3 full-text file(s): application/pdf | application/pdf | application/vnd.openxmlformats-officedocument.wordprocessingml.document |
| Rights | 3 full-text file(s): info:eu-repo/semantics/closedAccess | info:eu-repo/semantics/openAccess | info:eu-repo/semantics/openAccess |
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