Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model

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Abstract

Macrophages infiltrating the allografts are heterogeneous, consisting of pro-inflammatory (M1 cells) as well as anti-inflammatory and fibrogenic phenotypes (M2 cells); they affect transplant outcomes via diverse mechanisms. Herein, we found that macrophage polarization into M1 and M2 subsets was critically dependent on TRAF6 and mTOR, respectively. In a heart transplant model we showed that macrophage-specific deletion of TRAF6 (LysM Cre Traf6 fl/fl) or mTOR (LysM Cre Mtor fl/fl) did not affect acute allograft rejection. However, treatment of LysM Cre Mtor fl/fl recipients with CTLA4-Ig induced long-term allograft survival (>100 days) without histological signs of chronic rejection, whereas the similarly treated LysM Cre Traf6 fl/fl recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4-Ig treated LysM Cre Traf6 fl/fl mice was similar to that of CTLA4-Ig treated wild type B6 recipients. Mechanistically, we found that the graft infiltrating macrophages in LysM Cre Mtor fl/fl recipients expressed high levels of PD-L1, and PD-L1 blockade readily induced rejection of otherwise survival grafts in the LysM Cre Mtor fl/fl recipients. Our findings demonstrate that targeting mTOR-dependent M2 cells is critical in preventing chronic allograft rejection and that graft survival under such conditions is dependent on the PD-1/PD-L1 co-inhibitory pathway.

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Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer.

Kristin Lastwika, Willie Wilson, Qing Li … (2016)

Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT-mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.

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Regulation of innate immune cell function by mTOR.

Thomas Weichhart, Markus Hengstschläger, Monika Linke (2015)

The innate immune system is central for the maintenance of tissue homeostasis and quickly responds to local or systemic perturbations by pathogenic or sterile insults. This rapid response must be metabolically supported to allow cell migration and proliferation and to enable efficient production of cytokines and lipid mediators. This Review focuses on the role of mammalian target of rapamycin (mTOR) in controlling and shaping the effector responses of innate immune cells. mTOR reconfigures cellular metabolism and regulates translation, cytokine responses, antigen presentation, macrophage polarization and cell migration. The mTOR network emerges as an integrative rheostat that couples cellular activation to the environmental and intracellular nutritional status to dictate and optimize the inflammatory response. A detailed understanding of how mTOR metabolically coordinates effector responses by myeloid cells will provide important insights into immunity in health and disease.

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Antonio Sica, Vincenzo Bronte (2007)

Tumors require a constant influx of myelomonocytic cells to support the angiogenesis and stroma remodeling needed for their growth. This is mediated by tumor-derived factors, which cause sustained myelopoiesis and the accumulation and functional differentiation of myelomonocytic cells, most of which are macrophages, at the tumor site. An important side effect of the accumulation and functional differentiation of these cells is that they can induce lymphocyte dysfunction. A complete understanding of the complex interplay between neoplastic and myelomonocytic cells might offer novel targets for therapeutic intervention aimed at depriving tumor cells of important growth support and enhancing the antitumor immune response.