STAT3- and STAT6-dependent cytokine interactions educate tumor-associated macrophages via induction of cathepsin proteases.

摘要

While macrophages are a fundamental element of the host innate immune system which constitutes the first line of defense against invading pathogens, tumor-associated macrophages (TAMs) have been shown to be co-opted by tumor cells and facilitate tumor initiation and progression. However, little is known about how TAMs acquire their tumor-promoting functions. One of the key pro-tumorigenic activities of TAMs is to provide proteases to the tumor microenvironment, including cysteine cathepsin proteases. We hypothesized that TAMs are educated by the cellular interactions within the tumor microenvironment, leading to the induction of their high cathepsin activity. The objective of my thesis research is to gain mechanistic insights into how complex cell-Cell interactions shape this phenotype of TAMs, and to investigate the significance of the intercellular communications in tumorigenesis.;Consistent with our hypothesis, we found that interleukin-4 which is supplied by tumor cells and T cells, can induce cathepsin activity in TAMs. In addition, we also discovered the interaction between STAT3- and STAT6-dependent cytokine signaling pathways that leads to a synergistic induction of cathepsin secretion in macrophages. In order to elucidate the roles of these cellular interactions in tumorigenesis, we took a genetic approach to dissect the contributions of STAT3- and STAT6-mediated cytokine signaling pathways in different cell types to tumor development and progression in the RIP1-Tag2 (RT2) model of pancreatic islet carcinogenesis. Our results revealed significant contributions to tumorigenesis from non-tumor cell-autonomous effects of both pathways.;Together, our studies illustrate how the complex reciprocal intercellular interactions in the tumor microenvironment can significantly impact tumorigenesis, and also indicate the potential of these tumor-stromal cytokine signaling pathways as targets for cancer therapy.