Macrophage Proliferation Machinery Drives Immunosuppression and PDAC Progression (巨噬细胞增值机制抑制肿瘤免疫促进胰腺癌发展)
Date of Award
Doctor of Philosophy (PhD)
Tumor-associated macrophages (TAMs) are abundant in near all solid tumors and are involved in many aspects of cancer progression. The presence of TAMs is negative prognostic indicator in several cancer types including pancreatic cancer. Attempts to target this population by limiting their number in PDAC tumors have not achieved promising results, as compensatory resistance pathways have already been defined. The heterogeneity of TAMs puts another barrier into this targeting strategy, given macrophage subsets are important in maintaining tissue homeostasis and some in performing anti-tumor functions. Previous studies have shown that TAMs in PDAC tumors have dual origins – HSC-derived and embryonic-derived. Both subsets of TAMs expand during tumor development and potentially have distinct functions. However, the impact local proliferation might have on macrophage phenotype and cancer progression has not been demonstrated. Here, we utilized genetically engineered cancer models, single-cell RNA-sequencing data, and in vitro systems to show that proliferation of TAMs was driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. We further found that a negative regulator of cell-cycle machinery, p21, was also induced by CSF-1 signaling pathway. TAMs in human and mouse PDAC with high levels of p21 acquired a more inflammatory yet immunosuppressive phenotype. The p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo promoted tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression, also cause responsive to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell-cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy.
Chair and Committee
Zuo, Chong, "Macrophage Proliferation Machinery Drives Immunosuppression and PDAC Progression (巨噬细胞增值机制抑制肿瘤免疫促进胰腺癌发展)" (2022). Arts & Sciences Electronic Theses and Dissertations. 2697.