Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade

Abstract

ObjectiveIn the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models.DesignWe analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and OPNknockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC.ResultsThe numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPNhigh tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8+ T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC.ConclusionsOPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.

Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib

“…9 10 Macrophages are critical in HCC pathogenesis. 10 In general, macrophages can be polarized to M1 or M2 status in response to various signals. 11 Classically activated macrophages, known as M1 (lipopolysaccharide (LPS) or interferon (IFN)-γ activated), produce proinflammatory and immunostimulatory cytokines (interleukin (IL)-1β, tumor necrosis factor (TNF)-α, INF-β1 and so on) to participate in antigen presentation and resultant anti-tumorigenic Open access activity.…”

Prognostic and Immunological Role of FUN14 Domain Containing 1 in Pan-Cancer: Friend or Foe?

“…On the one hand, unlike the conventional view of immune cells as a component of an antitumor strategy, immune infiltration into the TME reflects a tactic tumor cells use to avoid being killed (13)(14)(15). For example, tumor-associatedmacrophages (TAMs) can help tumor cells in several ways, including immune escape, tumor angiogenesis, and metastasis (16)(17)(18)(19). In addition, aside from macrophages, almost all types of immune cells, including B cells, CD8+ T cells, CD4+ T cells, neutrophils, natural killer (NK) cells, and dendritic cells (DC), are found in the TME, and some participate in the development of cancers (12).…”

Inflammatory Mechanisms of HCC Development

“…HCC cells play a key role in inducing the differentiation of circulating monocytes in M2 pro-tumor macrophages through the secretion of specific cytokines and growth factors, such as IL-4, IL-13, CSF-1 (Colony Stimulating Factor-1), CTGF (Connective Tissue Growth Factor) [60,99] (Table 1). Moreover, Osteopontin, secreted by HCC cells, induces both PD-L1 expression and attraction of M2 in the tumor site [100]. TAMs together with MDSCs, through the down regulation of immune-permissive IL-6 and IL-12 and over-expression of immune-suppressive IL-10, reduce both innate and adaptive immunity by impairing CD8+ T cells and NK cells respectively [101].…”