Interaction between tumor and host immune and hematopoietic system using mouse models and human samples
The research of our laboratory for the past few years has been focused on the role of tumor-derived factors in hematopoietic development, immune cell differentiation and function. These studies broadly relate to cancer biology, cancer immunology, tumor-host interaction, and tumor microenvironment. They are aimed on understanding the molecular mechanisms of carcinogenesis, immune suppression, hematopoietic/immune development in cancer, and the mechanisms exploited by tumor to convert tumor-infiltrating cells from protective to tumor supporting factor.
We identified adenosine as an important tumor metabolite that alters differentiation and function of tumor-infiltrating immune cells by activating A2B adenosine receptor. It induces recruitment of myeloid-derived suppressor cells and secretion of tolerogenic and angiogenic factors including VEGF by tumor immune infiltrate. Our research is focused on understanding the molecular mechanisms of adenosine effects and the development of therapeutic strategies to target the A2B adenosine receptor in cancer. This receptor is an especially attractive target for therapy, as due to its low affinity to adenosine it stays silent under normal conditions and becomes active only at pathologically high adenosine levels.
Defects in T cell function are evident in tumor bearing hosts. We found that tumor-associated defects in T cell development are characterized by attenuated levels of delta-like (DLL) 1 and DLL4 in the bone marrow (BM) microenvironment, and elevated circulating VEGF is one causative factor. We also revealed that elective therapeutic stimulation of Notch signaling in animals using multivalent form of DLL1 significantly reduces tumor growth, rescues T cell development and enhances T cell-mediated immune responses and that over-expression of DLL1 alone in BM precursors also inhibits tumor growth and improves anti-tumor immunity. Using mouse models, we selectively stimulated VEGFR1 and VEGFR2 by continuous infusion of receptor-specific ligands or selectively blocked their signaling with VEGF receptor-specific antibodies in mice infused with recombinant VEGF to demonstrate that activation of VEGFR1 and VEGFR2 has selective effects on differentiation and function of various lymphoid and myeloid lineages.
Our ultimate goal is to develop and validate the novel therapeutic strategies targeting the identified mechanisms to correct tumor-induced aberrant hematopoietic differentiation and immune deficiency.