The effect of the tumor microenvironment on myeloid cells.

Abstract

Immune responses are important for determination of tumor fate. My laboratory has been studying the interactions between Human Papillomavirus (HPV) associated tumors and the immune system. In the tumor microenvironment, where cytokines, metabolites and several other factors play a role, myeloid cells can display tolerogenic phenotype, inhibiting T cell responses. Tumors also display systemic effects on the immune system, one of them is leukocytosis. We have previously shown that HPV transformed cells secrete cytokines as IL-6 and G-CSF and the patients with cancer display an increase in the number of circulating myeloid cells. Moreover, we have shown a negative correlation between the frequency of neutrophils and T cells in tumors and, in vitro, observed that neutrophils, in the presence of tumor cells, could inhibit T cell activity. These results corroborate the evidence of a microenvironment that promotes tolerance. Interestingly, we have also shown that monocytes that differentiated into macrophages in the tumor microenvironment acquired a M2 biased phenotype, induced, in part, by lactate secreted by tumor cells. Therefore, we have been working with the premise that the tumor microenvironment signals systemically to promote the accumulation of myeloid cells, which are recruited and modulated in the tumor, becoming tolerogenic and, ultimately promoting tumor growth. With this working model in mind, our objective is to further investigate the molecular mechanisms in the interactions between tumor cells and myeloid cells from healthy and cancer bearing donors. With this work, we hope to find therapeutic opportunities against HPV associated cancers, which may be used also in other myeloid cells rich cancers. (AU)