AbstractMacrophages play central roles in different diseases and pathologies, ranging from arthritis to cancer and diabetes. They are very plastic cells, whose phenotypes are steered by their microenvironment. Insights in their phenotype and its driving factors could give rise to potential therapies wherein these cells could be modulated.
In this PhD, we first focused our attention on the macrophages in tumors, called tumor-associated macrophages or TAM. These were already shown to consist of molecularly and functionally distinct subpopulations, termed MHC-IIlo and MHC-IIhi TAM, both derived from Ly6Chi monocytes. Here, we demonstrate that M-CSFR is involved in the recruitment, extravasation, proliferation and maturation of the Ly6Chi monocytic precursors. Blocking with anti-MCSFR Ab resulted in a reduction of mature TAM. In addition, M-CSFR signaling blockade led to an altered MHC-IIlo/MHC-IIhi TAM balance by modulating the preferential differentiation of Ly6Chi monocytes. GM-CSFR had no role in the recruitment or differentiation of Ly6Chi monocytes, but did play an important part in the fine-tuning of the MHC-IIhi TAM phenotype.
Although much is already known about the TAM subsets and their molecular phenotype, their interaction with the microenvironment through the production of chemokines remained largely uncharacterized. Indeed, the TAM subsets showed differential production of chemokines, with more monocyte-attracting chemokines for the MHC-IIlo TAM and more lymphocyte-attracting chemokines for the MHC-IIhi TAM. The chemokine CCL17 was clearly associated with the MHC-IIhi TAM in all examined tumor models, but had no clear effect on tumor growth in a lung carcinoma model. The MHC-IIlo TAM, on the other hand, abundantly produced CCL8. Abrogating this chemokine’s receptor, CCR8, led to an enhanced inflammatory response in tumors, leading to a slowed tumor growth. Depletion of T cells reverted this phenotype back to the WT situation, establishing an important anti-tumoral role for these cells. This demonstrates that the CCL8-CCR8 axis sustains an immunosuppressive tumor microenvironment. Both M-CSFR and CCR8 could serve as potential targets for therapy, and M-CSFR has actually already shown evidence of clinical efficacy.
We broadened our research span by examining pancreas macrophages both in the naive and injured pancreas. Interestingly, we could identify very similar macrophage subpopulations in the pancreas compared to the tumor. After wounding, there was an early surge of Ly6Chi monocyte infiltration in the pancreas, followed by a transient MHC-IIlo macrophage peak and ultimately a restoration of the MHC-IIhi macrophage dominated steady state equilibrium. These MHC-IIlo and MHC-IIhi macrophages were a mix of tissue-macrophages and monocyte-derived macrophages, with phenotypes that were reminiscent of the TAM subsets. These data demonstrate a more general existence of MHC-IIlo and MHC-IIhi macrophage subsets in different organs. In addition, we illustrated a role for M-CSFR in the differentiation of these macrophages in this model, suggesting a potential broader applicability of anti-MCSFR mAbs or inhibitors.
In conclusion, this works reveals insights in the biology of macrophages in different microenvironments and draws parallels between them. Moreover, it identifies potentially interesting targets for immunotherapy.
|Date of Award||8 Dec 2015|