Date of Award

Spring 5-15-2022

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

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.

肿瘤相关的巨噬细胞 (TAM)广泛存在于几乎所有实体瘤中,并且参与癌症发生发展的许多方面。TAM的浸染和很多包括胰腺癌在内的病人存活率呈负相关。之前尝试通过抑制巨噬细胞存活信号通路减少其数量的研究并没有产生太多的临床效果,因为肿瘤会很快找到逃脱途径。巨噬细胞的异质性使得针对这个细胞类群为靶点的药物无法有效甄别和去除只是促进肿瘤生长的巨噬细胞子集。研究表明,巨噬细胞在胰腺中有两种起源,一种通过血液中的单核细胞,另外一种通过胚胎时期产生的存在于组织中的巨噬细胞的增值。这两种来源的巨噬细胞在胰腺瘤中都保持增值的能力。但是至今没有研究直接解答增值本身是否影响胰腺肿瘤中巨噬细胞的总数,以及胰腺癌的发展。这篇毕业论文作者通过新建立的小鼠模型,单细胞测序,体外细胞共培养等方式,发现肿瘤中成纤维细胞分泌的CSF1诱导巨噬细胞的增值,同时独立于巨噬细胞增值,上调细胞周期负调控因子,p21的表达。p21表达本身可以激活炎症信号以及免疫抑制信号通路。p21表达在小鼠模型中直接改变巨噬细胞表现型,同时促进胰腺癌肿瘤增长。更有趣的是,相同的p21诱导的炎症免疫抑制通路的激活增强了CD40激动剂和化疗药物连用的作用。综上所述,本文阐述了,基质或治疗诱导的细胞周期因子的表达可以调节巨噬细胞介导的免疫抑制和对先天免疫疗法的敏感性。

Language

English (en)

Chair and Committee

David DeNardo

Committee Members

Daniel Link

Included in

Biology Commons

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