Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer

Abstract

Abstract TGFβ is a pleotropic cytokine, which has emerged as a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. There are three isoforms of TGFβ (TGFβ1, TGFβ2 and TGFβ3), which are secreted by immune and nonimmune cells as an inactive latent complex. Depending on the local context and players, TGFβ can adopt opposing roles in carcinogensis and in modulating the immune system. However, the expression of TGFβ isoforms within the tumor microenvironment and isoform specific inhibition remains to be investigated. The main source of TGFβ isoforms in the tumor microenvironment of B16 melanoma are infiltrating immune cells, with TGFβ1 and TGFβ3 being highly expressed on myeloid and dendritic cells. The CD45− population from B16 tumors demonstrated a lower expression of both TGFβ isoforms. Compared to untreated control animals, anti-TGFβ3 therapy resulted in the greatest delay in B16 tumor growth, followed by anti-TGFβ1 therapy and pan-TGFβ blockade. However, none of the therapies resulted in improved overall survival. Similar results were achieved in a 4T1 breast model. T cell functional assays demonstrated that anti-TGFβ3 resulted in CD8+ T cells with greater cytolytic ability as they showed higher granzyme B expression and killing against B16 cells when plated ex-vivo. Anti-TGFβ1 treatment resulted in greater interferon-γ production by CD8+ T cells, suggesting an increase in antigen-specificity. Isoform specific TGFβ inhibition in combination with immune checkpoint blockade demonstrated improved tumor control and survival. This provides rationale for the use of anti-TGFβ therapy in stroma poor tumors, such as melanoma, and for its potential to enhance the effectiveness of existing therapies.