Author ORCID Identifier

0000-0001-8242-3880

Date of Graduation

5-2021

Document Type

Thesis (MS)

Program Affiliation

Biochemistry and Molecular Biology

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Dihua Yu, Ph.D., M.D.

Committee Member

Jason Huse, Ph.D., M.D.

Committee Member

Min Gyu Lee, Ph.D.

Committee Member

Pierre McCrea, Ph.D.

Committee Member

Shao-Cong Sun, Ph.D.

Abstract

Breast cancer brain metastases have remained one of the most intense challenges for precision cancer therapeutics, but current treatment options are limited and not curative. Recently, our lab reported that adoptive PTEN downregulation in metastatic breast tumor cells activates PI3K/NF-ƙB signaling and increases the secretion of the chemokine CCL2, which enhances the chemotaxis of CCR2+ myeloid cells, a major subpopulation of bone marrow-derived myeloid cells (BMDMs), from peripheral blood into the brain tumor microenvironment (TME), eventually promoting brain metastasis outgrowth by driving immune suppression. Here, in this project we have been aiming to develop effective therapies by immune-modulating the roles of the CCL2-CCR2 signaling axis in immune dysregulation in brain metastasis. We demonstrated that CCR2 antagonism cannot sufficiently impede breast cancer brain metastasis in multiple preclinical models, including two syngeneic immunocompetent models and a CCR2-deficient model, although the CCR2 antagonist PF-04136309 significantly blocks monocyte trafficking in blood and CCR2+ myeloid cell infiltration into the brain TME. Our data provides great caution for targeting CCR2+ myeloid cells in the TME, since blockade of the CCL2-CCR2 axis has been a popular area of interest in therapy development for many other cancer types, suggesting the clinical outcome of CCR2 antagonists may be highly context-dependent. Moreover, we showed that CCL2 upregulation promotes brain metastasis in the newly-established WHIM3 PDX TNBC model, which sheds light on potential therapeutic opportunities of our targeting elevated CCL2 secretion for brain metastasis patients. Overall, our findings provide a new preclinical rationale for further exploration into the immune-modulation of the CCL2-CCR2 signaling axis for cancer therapy development.

Keywords

CCR2, CCR2 antagonist, Breast cancer, Brain Metastasis, CCL2-CCR2 signaling axis, Heterogeneity, PDX model

Available for download on Thursday, April 28, 2022

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