12P - Immuno-suppressive role of tumour-derived GDF-15 on myeloid cells

Background

Growth and differentiation factor 15 (GDF-15), a divergent member of the TGF-β superfamily, shows high expression during pregnancy. Beyond that, GDF-15 is induced in stressed and damaged tissues limiting inflammation. GDF-15 also functions as a prognostic marker in numerous cancers and was shown to be a key inhibitor of T-cell infiltration in solid tumors. However, the impact of GDF-15 on other immune cells in the tumor microenvironment (TME) is still poorly understood.

Methods

M1 and M2 macrophages were derived from either the human monocytic THP-1 cell line or monocytes from healthy donors by incubation with IFNγ and LPS (M1) or IL-4 and IL-13 (M2) in combination with or without GDF-15. Analysis was performed by Western Blot, flow cytometry and RT-qPCR. To investigate the role of GDF-15 in vivo we inoculated NOG mice subcutaneously with SK-Mel5 GDF15 ^-/- cells. On day 35/36 tumors were assessed on myeloid immune cell subpopulations by flow cytometry.

Results

Our initial studies have shown that monocytes are sensitive to GDF-15 mediated inhibition of tumor infiltration. Now we wanted to understand how GDF-15 affects the myeloid compartment beyond infiltration. In primary cells, GDF-15 exposure of monocytes during IFNγ or LPS induced M1 polarization led to a reduction of activation marker expression such as HLA-DR, CD80 and CD86 and an altered cytokine secretion profile. M2 macrophages did not show differences in their activation pattern. This effect was transferable to THP-1 derived M1 macrophages. TGF-ß was not able to exert this biologic effect. Activation was restored by addition of a GDF-15 neutralizing antibody. In vivo, GDF-15 had no direct effect on tumor growth, yet we observed that loss of GDF-15 altered the TME and led to an increase of activated myeloid cells such as M1 macrophages and dendritic cells.

Conclusions

GDF-15 secretion helps tumors to generate a TME that is poorly infiltrated by anti-tumoral immune cells. GDF-15 counteracts myeloid activation in the TME, a hallmark of initiation of antitumoral immune responses. By inducing a more pro-inflammatory tumor phenotype, anti-GDF-15 antibodies may synergize with other immunotherapeutic agents. A clinical phase 2 trial combining anti-GDF-15 (CTL-002) with anti-PD-1 (NCT04725474) is ongoing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

CatalYm GmbH.

Funding

CatalYm GmbH.

Disclosure

C. Schuberth-Wagner: Financial Interests, Personal, Full or part-time Employment: CatalYm GmbH; Financial Interests, Personal, Stocks/Shares: CatalYm GmbH, Merck & Co; Financial Interests, Personal, Royalties: Rigontec GmbH; Non-Financial Interests, Advisory Role: RNHale GmbH. I. Giese, M. Kist, N. Vashist, S. Genßler, M. Auer, K. Klar: Financial Interests, Personal, Full or part-time Employment: CatalYm GmbH. J. Weigandt: Financial Interests, Personal, Full or part-time Employment, Scientist Role: Catalym; Financial Interests, Personal, Stocks/Shares, small number of shares held privately: AstraZeneca, Moderna. J. Wischhusen: Financial Interests, Personal, Advisory Board: CatalYm; Financial Interests, Personal, Stocks/Shares: CatalYm; Financial Interests, Personal, Advisory Board, Fees received via University of Würzburg as compensation for inventorship: CatalYm; Financial Interests, Institutional, Funding: CatalYm. E. Leo: Financial Interests, Personal, Advisory Board, Advisory role: T-knife GmbH; Financial Interests, Personal, Full or part-time Employment, CMO: CatalYm GmbH; Financial Interests, Personal, Stocks/Shares, Share options: CatalYm GmbH, T-knife GmbH. M. Haake: Financial Interests, Personal, Full or part-time Employment: CatalYm GmbH; Financial Interests, Personal, Stocks/Shares, Co-Founder: CatalYm GmbH; Financial Interests, Personal, Advisory Board: CatalYm GmbH; Non-Financial Interests, Other, Co-founder: CatalYm GmbH. All other authors have declared no conflicts of interest.