Carcinomas exhibit remarkable plasticity and may undergo profound phenotypic changes during progression towards metastasis. These changes, collectively termed “carcinoma mesenchymalization,” involve the acquisition of mesenchymal features; invasiveness and propensity to disseminate; acquisition of stemness features, including a relatively quiescent state; and conversion into a refractory, therapy-resistant state. In search of drivers of the mesenchymalization phenomenon that could be targeted via immunotherapy, our laboratory previously identified the embryonic T-box transcription factor brachyury as a tumor-associated antigen that is highly expressed in various human carcinomas, including lung and triple-negative breast cancer and in the rare tumor type chordoma, among others. High brachyury levels at the primary tumor site have now been shown to associate with poor survival in patients with various cancer types. Two vector-based cancer vaccine platforms developed against brachyury, a yeast-brachyury and a poxvirus-based MVA-brachyury-TRICOM vaccine, have now completed phase I clinical evaluation, both demonstrating safety and the ability to significantly expand brachyury-specific CD4+ and CD8+ T cells in vaccinated patients. Based on evidence of clinical activity in patients with chordoma, the yeast-brachyury vaccine is currently being evaluated in a randomized, double-blind phase II study of radiation +/- vaccine in this rare tumor type. An emerging concept in the field of tumor immunology is that mesenchymalization may also confer resistance to antitumor immune responses. Our laboratory has shown that human carcinoma cells undergoing mesenchymalization exhibit decreased susceptibility to lysis mediated by immune effector cells, including antigen-specific CD8+ T cells, innate natural killer (NK) cells, and lymphokine-activated killer (LAK) cells. Based on these observations, we are currently investigating potential strategies aimed at blocking tumor microenvironment-derived signals that control phenotypic plasticity, with the ultimate goal of combining these approaches with immunotherapy. The chemokine interleukin-8 (IL-8) is overexpressed in multiple cancer types, where it promotes the acquisition of mesenchymal features, stemness, resistance to therapies, and the recruitment of immune-suppressive cells to the tumor site. We have now shown that blockade of the IL-8/IL-8R axis is effective at reverting the phenotype of the tumor cells towards a more epithelial one, decreasing stemness features, and significantly enhancing tumor sensitivity to chemotherapy, small-molecule targeted therapies, and immune-mediated lysis with NK and antigen-specific T cells in vitro. These results formed the rationale for using anti-IL8 approaches in combination with cytotoxic or immune-based therapies for the treatment of advanced cancer.
Citation Format: Claudia Palena, James L. Gulley, Jeffrey Schlom. Brachyury and the interleukin-8 axis in tumor progression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN07-03.