Our laboratory has previously identified the T-box transcription factor brachyury as a driver of human carcinoma EMT. We have shown that high levels of expression of brachyury drive carcinoma cells into a mesenchymal-like phenotype, increase tumor cell motility and invasiveness in vitro, and enhance tumor cell dissemination in vivo in animal models. High levels of brachyury have been reported in various types of carcinomas, including lung, colon, prostate and breast, and our laboratory has recently demonstrated the predominant overexpression of this embryonic transcription factor in triple negative breast cancer (TNBC). High levels of brachyury have been also shown in small cell lung carcinomas, germ cell tumors (both embryonal and seminomas), a fraction of glioblastomas and the rare tumor type chordoma. Three brachyury-targeting cancer vaccines developed in our laboratory in collaboration with the private sector are currently undergoing clinical evaluation, including (1) a yeast-brachyury vaccine currently undergoing Phase II clinical evaluation in patients with chordoma; (2) an adenovirus-brachyury vaccine; and (3) a poxviral vector-based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM). The study of brachyury as a tumor-associated antigen and its role as a driver of tumor phenotypic plasticity led our laboratory to demonstrate that carcinoma cells bearing mesenchymal features are resistant to the cytotoxic effect of immune effector cells. These observations imply that changes in tumor phenotype induced by expression of very high levels of brachyury could have a negative impact on the various immune-based interventions against cancer that are currently being investigated in the clinic, all of which ultimately rely on the ability of effector immune cells to efficiently lyse cancer cells. Multiple tumor intrinsic or extrinsic factors, including cytokines, chemokine and growth factors, could induce EMT in tumor cells. We have now demonstrated that the chemokine IL-8 is overexpressed in multiple cancer types, including triple-negative breast cancer (TNBC), where it promotes the acquisition of mesenchymal features, stem-cell like properties, resistance to therapies, and the recruitment of immune-suppressive cells to the tumor site. In initial studies conducted with a clinical-stage monoclonal antibody that neutralizes IL-8, our laboratory demonstrated that blockade of IL-8 can (1) revert tumor plasticity in models of triple negative breast cancer, both in vitro and in vivo; (2) significantly decrease the recruitment of granulocytic myeloid-derived suppressor cells (G-MDSCs) at the tumor site; and (3) enhance the susceptibility of breast cancer cells to immune-mediated lysis with NK and antigen-specific T cells in vitro. One of the tumor types with a high degree of infiltration with G-MDSCs is head and neck carcinoma (HNSCC), a tumor type where IL-8 has also been shown to be relevant to the biology of the disease. In collaboration with Dr. C. Allen (NIDCD), we have evaluated the potential effect of IL-8 signaling blockade via inhibition with a small molecule inhibitor of IL-8 receptors, CXCR1 and CXCR2, in models of HNSCC. The results of these studies demonstrated that inhibition of CXCR1/2 can decrease tumor accumulation of G-MDSCs and enhance the efficacy of PD-axis immune checkpoint blockade and adoptive cell transfer of engineered T cells. We expect that the results of this collaboration will provide the rationale for the clinical use of anti-IL8 strategies for the treatment of HNSCC tumors. Additional studies are being conducted in our laboratory to evaluate the use of IL-8 neutralizing antibodies or the small molecule inhibitor of CXCR1/2 in combination with various immunotherapeutic agents including checkpoint inhibitor antibodies, vaccines and other modulatory agents.
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