Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression

Although survival from breast cancer has dramatically increased, many will develop recurrent, metastatic disease. Unfortunately, the survival for this stage of the disease remains very low. Stimulating patients own immune systems against cancer cells has shown incredible curative potential in certain types of cancers and patients such as melanoma. However, immune checkpoint blockade (ICB) which works through T cells has had limited efficacy in breast cancer. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. Infiltration of immune-suppressive regulatory T cells (Treg) to the tumor microenvironment (TME) is associated with resistance to ICB. Tregs are a subset of CD4+ T cells known to be highly immune suppressive and associated with poor therapeutic response. Interestingly, within human breast tumors, NR0B2, a protein involved in cholesterol homeostasis, is inversely associated with FOXP3, a marker of Tregs. Myeloid intrinsic NR0B2 serves to decrease many aspects of the NLRP3 inflammasome, ultimately resulting in decreased IL1β; IL1β driving Treg expansion. Importantly, mice lacking NR0B2 exhibit accelerated tumor growth. Furthermore, we have developed NR0B2 as a potential therapeutic target. Small molecule agonists, including one developed here, reduced Treg expansion, reduced metastatic growth, and improved the efficacy of ICB. Together these findings demonstrate NR0B2 as a target to ‘re-educate’ myeloid immune cells and its potential utility in enhancing ICB. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular & Integrative Physi

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Vidana Gamage, Hashni Epa

Contributors dc:contributor

• Nelson, Erik R
• Ridlon, Jason M
• Hergenrother, Paul J
• Raetzman, Lori T

• Cholesterol
• Dshn-ome
• Nuclear Receptor
• Small Heterodimer Partner
• Treg.

Statement dc:rights

• ©2024 Hashni Epa Vidana Gamage

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/127425

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F127425