Neutralizing Tumor-Derived GDF-15 to Enhance T-Lymphocyte Infiltration and Cancer Immunotherapy Responses

Growth and differentiation factor 15 (GDF-15), a member of the TGF-β family, is typically low in healthy tissues but is produced in large amounts by the placenta during pregnancy to promote tolerance between mother and fetus. It is also increased in response to tissue damage, acting to prevent excessive immune responses. Notably, high levels of GDF-15 are found in various cancers, which are associated with worse outcomes and reduced survival.

In a study, immune cell subsets were treated with or without GDF-15 and then exposed to endothelial cells or adhesion molecules to assess their adhesion and migration. The effect of a GDF-15 neutralizing antibody (CTL-002) on T cell movement was also studied. In a humanized mouse model with implanted human melanoma cells, T cell infiltration was evaluated with and without CTL-002.

The results showed that GDF-15 significantly hindered the adhesion of T cells to endothelial cells, particularly affecting CD8+ T cells, while other immune cells were unaffected. The neutralizing antibody was able to counteract this effect. In the mouse model, using the antibody led to an increased number of tumor-infiltrating leukocytes, with a notable increase in T cells, especially CD8+ T cells.

The findings indicate that GDF-15's presence in tumors can impede T cell infiltration, a factor linked to better patient outcomes and response to immunotherapy. The use of a neutralizing antibody to target GDF-15 could potentially enhance the effectiveness of immunotherapies and improve survival rates for cancer patients. The study was presented by Markus Haake and colleagues at the 2020 Annual Meeting of the American Association for Cancer Research.