567 Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of stroma poor cancers

• Published in: Journal for immunotherapy of cancer 2021-11, Vol.9 (Suppl 2), p.A596-A596
• Main Authors: Budhu, Sadna, Gupta, Aditi, Fitzgerald, Kelly, Giese, Rachel, Michel, Adam, Holland, Aliya, Campesato, Luis Felipe, Snick, Jacques Van, Uyttenhove, Catherine, Ritter, Gerd, Wolchok, Jedd, Merghoub, Taha
• Format: Article
• Language: English
• Subjects: Immunotherapy; Melanoma; Regular and Young Investigator Award Abstracts; Tumors
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2021-SITC2021.567

BackgroundTGFβ is 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 non-immune cells as an inactive latent complex. Depending on the local context and players, TGFβ can adopt opposing roles in carcinogenesis and in modulating the immune system. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-rich tumors.MethodsWe examined expression of TGFβ1 and TGFβ3 isoforms on immune cells in two stroma-poor mouse tumor models (B16 melanoma and CT26 colon carcinoma) and investigated the anti-tumor efficacy of antibodies that block TGFβ1 and TGFβ3 in these two models.ResultsDepending on local expression of TGFβ isoforms, specific inhibition of either TGFβ1 or TGFβ3 may be effective. The ”TGFβ signature” of CT26 colon carcinoma is defined by TGFβ1 expression on immune cells and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both TGFβ1 or TGFβ3 isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. We show that the mechanism of tumor growth delay is enhanced CD8+ T cell activation and effector function. In addition, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control and survival.ConclusionsOur findings suggests that expression of TGFβ isoforms in the TME is variable in different tumor types and their expression may be used to predict anti-tumor responses to TGFβ inhibition. Isoform specific TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor regression alone or in combination with immune checkpoint blockade.