GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma

Abstract

BackgroundA better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment (TME) is crucial for developing more efficacious immunotherapies for hepatocellular carcinoma (HCC), which has a poor response to current immunotherapies. Regulatory T (Treg) cells are key mediators of HCC-associated immunosuppression. We investigated the selective mechanism exploited by HCC that lead to Treg cells expansion and to find more efficacious immunotherapies.MethodsWe used matched tumor tissues and blood samples from 150 patients with HCC to identify key factors of Treg cells expansion. We used mass cytometry (CyTOF) and orthotopic cancer mouse models to analyze overall immunological changes after growth differentiation factor 15 (GDF15) gene ablation in HCC. We used flow cytometry, coimmunoprecipitation, RNA sequencing, mass spectrum, chromatin immunoprecipitation and Gdf15–/–, OT-I and GFP transgenic mice to demonstrate the effects of GDF15 on Treg cells and related molecular mechanism. We used hybridoma technology to generate monoclonal antibody to block GDF15 and evaluate its effects on HCC-associated immunosuppression.ResultsGDF15 is positively associated with the elevation of Treg cell frequencies in patients wih HCC. Gene ablation of GDF15 in HCC can convert an immunosuppressive TME to an inflammatory state. GDF15 promotes the generation of peripherally derived inducible Treg (iTreg) cells and enhances the suppressive function of natural Treg (nTreg) cells by interacting with a previously unrecognized receptor CD48 on T cells and thus downregulates STUB1, an E3 ligase that mediates forkhead box P3 (FOXP3) protein degradation. GDF15 neutralizing antibody effectively eradicates HCC and augments the antitumor immunity in mouse.ConclusionsOur results reveal the generation and function enhancement of Treg cells induced by GDF15 is a new mechanism for HCC-related immunosuppression. CD48 is the first discovered receptor of GDF15 in the immune system which provide the possibility to solve the molecular mechanism of the immunomodulatory function of GDF15. The therapeutic GDF15 blockade achieves HCC clearance without obvious adverse events.

Coping With Stress: The Mitokine GDF-15 as a Biomarker of COVID-19 Severity

“…Candidate receptors for GDF-15 are ALK-5/TGF-bRII, TGF-bRI, TGF-bRII and the epithelial growth factor receptor ErbB2 (35)(36)(37). Recently, a new receptor for GDF-15, CD48, has been identified on Treg cells in a genetically-engineered mouse model (38). The GDF-15-CD48 interaction was shown to promote the propagation of Treg cells and indirectly upregulate forkhead transcription factor (Foxp3), enhancing the development of hepatocellular carcinoma (HCC) (38).…”

“…The GDF-15-CD48 interaction was shown to promote the propagation of Treg cells and indirectly upregulate forkhead transcription factor (Foxp3), enhancing the development of hepatocellular carcinoma (HCC) (38). This immunosuppressive tumor microenvironment was further shown to be altered by the introduction of monoclonal antibodies against GDF-15, which ultimately improved HCC control (38). Downstream signaling of GDF-15 has been studied in different models.…”

“…Recently, a new receptor for GDF-15, CD48, has been identified on Treg cells in a genetically-engineered mouse model ( 38 ). The GDF-15-CD48 interaction was shown to promote the propagation of Treg cells and indirectly upregulate forkhead transcription factor (Foxp3), enhancing the development of hepatocellular carcinoma (HCC) ( 38 ). This immunosuppressive tumor microenvironment was further shown to be altered by the introduction of monoclonal antibodies against GDF-15, which ultimately improved HCC control ( 38 ).…”

Transplanted Allogeneic Stem Cells Secrete GDF-15 and stimulate an Active Immune Remodeling Process in the Ischemic Myocardium

“…[28][29][30] Recently, CD48 is the rst discovered receptor of GDF15 in the immune system and is exclusively expressed on immune cells. 21 In co-culture experiment we looked for the uptake of rCPCs derived GDF15 by CD48 receptor on T-cells by ow. Data showed that all CD4 cells has CD48 receptor and the uptake of GDF15 by T-cells was signi cantly higher in rCPCs group as compared to control and rCPC-GDF15KD cells (Fig.…”

“…We have shown previously that CPCs secrete Growth Differentiation Factor 15 (GDF15) 8 , a cytokine produced in response to mitochondrial stress thought to contribute to adaptive homeostatic changes in response to tissue damage 16 . GDF15 has also peripheral anti-in ammatory/immunomodulatory and cardioprotective effects [17][18][19][20][21] . We hypothesized that transplanted allogeneic CPCs are immunomodulatory and exert cardioprotective effects similar to those observed with autologous CPCs.…”