Assessing The Outcomes of Blocking Ccl2-Ccr2 Signaling Axis On Breast Cancer Brain Metastasis

<p>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 <em>PTEN</em> 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.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2021

Authors dc:creator

• Qi, Yutao
• <p>0000-0001-8242-3880</p>

Contributors dc:contributor

• Dihua Yu, Ph.D., M.D.
• Jason Huse, Ph.D., M.D.
• Min Gyu Lee, Ph.D.

• CCR2
• CCR2 antagonist
• Breast cancer
• Brain Metastasis
• CCL2-CCR2 signaling axis
• Heterogeneity
• PDX model
• Cancer Biology
• Immunotherapy
• Laboratory and Basic Science Research
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1080

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2136