Influence of extramedullary monocytopoiesis in tumor progression: Characterization and relevance of cancer-induced inflammatory monocytes

• Applicant: Dr. Christina Pfirschke
• Subject Area: Hematology, Oncology ; Immunology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 236983298

Over the last decades it has become increasingly clear that the host immune system influences cancer progression. For example, tumor-associated macrophages (TAMs) frequently accumulate in high numbers in the stroma of solid tumors. TAMs promote malignant progression by different means, and it has been shown that the density of TAMs can also be used to predict the clinical outcome in human patients, i.e. more TAMs decrease patients survival. TAMs are continuously replaced by new precursor cells - inflammatory monocytes - that are recruited to the tumor site. Interestingly, monocytes can be made in distinct locations in the body. The bone marrow (BM) is the main site of monocyte production in steady state, however, during inflammation such as in cancer, extramedullary tissues can also produce monocytes. New findings have shown that the spleen constitutes a unique extramedullary developmental niche, and that large subpopulations of tumor-promoting TAMs originate from splenic monocytes. It is, however, currently unknown whether monocytes made in spleen or BM are the same, or if they are qualitatively different. In this proposal, I aim to test whether cancer-induced extramedullary monocytopoiesis produces cells with unique functions. I will characterize the phenotype and function of monocytes produced in spleen and BM in steady state and during cancer progression (Aim 1). Moreover, I will ask if spleen- and BM-derived monocytes, once recruited to tumors, give rise to functionally distinct TAM subpopulations (Aim 2). The investigations will be performed in a conditional genetic mouse model of lung adenocarcinoma, which recapitulates the human disease closely, and will use in vitro assays and state-of-the-art in vivo cell tracking approaches. Revealing the functional capabilities of splenic monocytes will provide new insights into how the host immune response is shaped during tumor progression. Moreover, a better understanding of TAM precursors - rather than TAMs themselves - should help to identify novel strategies for suppressing TAM responses and thereby to control tumor progression.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Mikael J. Pittet