IFNα Potentiates Anti–PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment

Abstract

The overall response rate for anti-PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of interferon alpha (IFN-a) and anti-PD-1-based immunotherapy resulted in enhanced antitumor activity in unresectable HCC patients. In both immunocompetent orthotopic and spontaneous HCC models, IFN-a therapy synergized with anti-PD-1 and the combination treatment led to significant enrichment of cytotoxic CD27+ CD8+ T cells. Mechanistically, IFN-a suppressed HIF1a signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing the high-glucose microenvironment that fostered transcription of the T cell costimulatory molecule Cd27 via mTOR-FOXM1 signaling in infiltrating CD8+ T cells. Together, these data reveal that IFN-a reprograms glucose metabolism within HCC tumor microenvironment, thereby liberating T cell cytotoxic capacities and potentiating the PD-1 blockade-induced immune response. Our findings suggest that IFN-a and anti-PD-1 cotreatment is an effective novel combination strategy for HCC patients.

The presence of vessels encapsulating tumor clusters is associated with an immunosuppressive tumor microenvironment in hepatocellular carcinoma

“…IFN‐α is another protein belonging to the type I IFN family, which is currently used in cancer therapy, and it was thought that the direct inhibitory effects on tumor cell growth/functions were the major mechanisms important in the antitumor response in patients 24 . A combination of IFN‐α and anti‐PD‐1‐based immunotherapy resulted in enhanced antitumor activity in patients with unresectable HCC 25 . In addition, antigen contact with the BCR and subsequent signal transduction are the initial steps for B cell activation and proliferation, 26 and intertumoral B cells located in a tertiary lymphoid structure may contribute to the antitumor activity of immunotherapy 27 …”

“…24 A combination of IFN-α and anti-PD-1-based immunotherapy resulted in enhanced antitumor activity in patients with unresectable HCC. 25 In addition, antigen contact with the BCR and subsequent signal transduction are the initial steps for B cell activation and proliferation, 26 and intertumoral B cells located in a tertiary lymphoid structure may contribute to the antitumor activity of immunotherapy. 27 A heatmap representing the ssGSEA scores of those gene sets showed a clear tendency of VETC+ HCCs to aggregate on the side of lower scores of those immune-related gene sets (Figure 3).…”

ACAA2 was a predictor for the prognosis and immunotherapy response of hepatocellular carcinoma

“…The combined e cacy and safety of immunotherapy and antiangiogenic therapy for unresectable HCC have been con rmed in multiple studies [21]. IFNα and anti-PD1 cotreatment as a novel combination strategy for HCC has also been suggested [10]. A recent study demonstrated that perioperative camrelizumab plus apatinib displays promising e cacy and manageable toxicity in patients with resectable HCC [27].…”

Prospective approaches to enhancing CAR T cell therapy for glioblastoma

“…The pharmacologically selective inhibition of PTP1B using MSI-1436 induced the T cell-mediated tumor suppression and enhanced PD-1 blockade response ( 47 ). Moreover, a combination of anti-PD-1-based immunotherapy with IFN-α resulted in encouraging anticancer activity in unresectable HCC patients ( 52 ). In infiltrating CD8 + T cells, IFN-α downregulates the ability to consume glucose and consequentially establishes a high glucose microenvironment promoting the transcription of CD27, which is the T cell costimulatory molecule.…”