Developing Novel Therapies Targeting the Tumor Microenvironment of Aggressive Breast Cancer

<p>Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive breast cancer subtypes. The tumor microenvironment (TME) is critical in driving these aggressive breast cancers' clinical phenotype and aggressiveness. Therefore, we explored novel actionable targets and complementary therapies targeting the TME to improve the outcomes of patients with these cancers.</p> <p>In this thesis, we identified AXL as a potential therapeutic target in IBC due to its role in generating an immunosuppressive TME. Indeed, inhibiting the AXL pathway suppresses IBC tumor growth and reduces M2 macrophage populations in various mouse models. Mechanistically, AXL facilitates the polarization of M2 macrophages and enhances the expression of immunosuppressive molecules and chemokines through the mediation of the transcription factor STAT6, subsequently accelerating the growth and migration of IBC cells. Intriguingly, CIBERSORT deconvolution showed that high AXL expression is correlated with an immunosuppressive TME, including the larger population of M2 macrophages, in tumor tissues from patients with IBC.</p> <p>Next, to enhance the efficacy of AXL-targeted therapy, we conducted a synthetic lethal kinome siRNA screening in vitro to identify novel synergy targets. We found TANK-binding kinase 1 (TBK1) to be the top therapeutic candidate due to its critical role in immune responses. Strikingly, combined suppression of AXL and TBK1 significantly reduces IBC and TNBC growth in vitro and in vivo by modulating the immunosuppressive TME. Mechanistically, TBK1 induces IRF3-regulated CCL5 secretion in cancer cells, which generates the paracrine effects with AXL-regulated CCR5 in M2 macrophages and consequently suppresses the recruitment of cytotoxic T cell population.</p> <p>In conclusion, targeting AXL alone or in combination with TBK1 represents potentially effective therapies through modulating the TME of aggressive breast cancer, which warrants further investigation in the clinical setting to improve patient outcomes.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Phi, Lan T H
• <p>https://orcid.org/0000-0003-3967-2747</p>

Contributors dc:contributor

• Naoto T. Ueno, M.D., Ph.D.
• Anil K. Sood, M.D.
• James M. Reuben, Ph.D., M.B.A.

• Aggressive Breast Cancer
• Tumor Microenvironment
• Novel Therapies
• Cancer Biology
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1418

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2475