Abstract 1549: Undesirable metastasis-stimulating effects of anti-TGF-β therapy in breast cancer models involve interference with tumor cell-autonomous tumor suppressive activity

Abstract

Abstract TGF-βs are central regulators of normal tissue homeostasis and response to stress and injury. Dysregulation of this pathway occurs frequently in cancer, and overexpression of TGF-βs in many advanced human tumors correlates with metastasis and poor prognosis. Preclinical studies have shown that TGF-β antagonists can slow tumor progression, largely by reactivating anti-tumor immunity, and there are now >45 ongoing or completed early phase clinical oncology trials using TGF-β antagonists. However, TGF-βs also have tumor suppressive activities, although these are conventionally considered to be restricted to the early stages of tumorigenesis. Most preclinical studies have focused on a very small number of widely used tumor models distributed across many different disease sites. Here we have assembled a panel of twelve immunocompetent mouse allograft models of metastatic breast cancer to capture some of the heterogeneity of the human disease within one disease histology. We find heterogeneous responses of these models to treatment with a neutralizing anti-TGF-β antibody, using lung metastatic burden as the clinically relevant endpoint. Anti-TGF-β antibody treatment inhibited metastasis in 5 models (InhibMet), had no effect in 4 models (NoEff) and showed an undesirable stimulatory effect on metastasis in 3 models (StimMet). As seen previously, the therapeutic effect in the InhibMet models was dependent on an intact immune system. However, the metastasis stimulatory effect in the StimMet models was immune-independent. Transcriptomic analysis of untreated primary tumors showed that InhibMet models had highest expression of a cytotoxic T-cell signature, and higher levels of infiltrating CD8 T-cells were detected by immunohistochemistry, suggesting that a therapeutic response to TGF-β antagonism may depend on some level of pre-existing immune response. In the MVT1 StimMet model, blockade of TGF-β signaling in the tumor cell using a dominant negative TGF-β receptor increased metastasis, suggesting that TGF-β antagonists can interfere with metastasis-suppressing effects of TGF-β on the tumor parenchyma. Consistent with this finding, the StimMet models showed higher expression of an independently-derived TGF-β gene signature that specifically reflects tumor suppressive responses to TGF-β in the tumor cell. In vitro, TGF-β suppressed clonogenicity and tumorsphere formation in all StimMet models but not InhibMet models, suggesting that suppressive effects of TGF-β may target the cancer stem cell population in the StimMet models. Thus our data suggest that contrary to dogma, tumor suppressive effects of TGF-β may still be active in some cases of advanced metastatic disease. Good predictive biomarkers will be essential to exclude patients who might experience deleterious responses to anti-TGF-β therapy. Note: This abstract was not presented at the meeting. Citation Format: Yu-an Yang, Howard Yang, Binwu Tang, Alex Wu, Nellie Moshkovich, Maxwell Lee, Lalage Wakefield. Undesirable metastasis-stimulating effects of anti-TGF-β therapy in breast cancer models involve interference with tumor cell-autonomous tumor suppressive activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1549.