Abstract
Abstract The tumor microenvironment (TME) plays a critical role in cancer proliferation, metastasis, & responses of patients to treatment. Within the TME, tumor-initiated signaling results in aberrant activation of stromal & immune cell populations to suppress immune surveillance, induce angiogenesis, & establish premetastatic niches. Macrophages, a subset of antigen presenting myeloid cells, are the most abundant immune cell in the TME & participate in immune regulation during tumorigenesis. They functionally exhibit both anti & pro-tumorigenic properties as well as demonstrate the plasticity to repolarize between phenotypes based on environmental cues. Additionally, macrophage subset predominance within the TME & tumors have been correlated to favorable prognoses in some cancers. However, there is a lack of consensus for their role in colorectal cancer (CRC) progression. In this study, we investigated CRCs with distinct mutations, grade, & origin for their ability to drive macrophage differentiation & function in vitro. Human CRC cells were used to create multicellular tumor spheroids to better recapitulate in vivo tumor biology. CD14 +monocytes were polarized into macrophage subsets (M 0/M1/M2) by cytokine/growth-factor exposure (GMCSF/MCSF/IFNγ/IL4/IL6/IL10) & co-cultured with each model. Spheroid proliferation & inflammatory profiles alone/in co-culture were assessed by live-cell microscopy, viability, & multiplex assays. Macrophage polarization, spheroid infiltration, & anti-tumor activity were examined by flow-cytometry, live-cell microscopy, & functional assessments. Overall, this study demonstrates that it may be useful to direct targeted therapies to influence macrophage polarization in CRC patients. Supported by funding from Janssen Pharmaceutical Companies of Johnson & Johnson, Inc. under the direction of the DPDS Postdoctoral Fellowship Program and Biologics Discovery Division - Exploratory Biology Department.
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