The immunomodulatory roles of small heterodimer partner and their implications in breast cancer progression

Shahoei, Sayyed Hamed

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https://hdl.handle.net/2142/109591 Copy

Description

Title

The immunomodulatory roles of small heterodimer partner and their implications in breast cancer progression

Author(s)

Shahoei, Sayyed Hamed

Issue Date

2020-11-29

Director of Research (if dissertation) or Advisor (if thesis)

Nelson, Erik R

Doctoral Committee Chair(s)

Nelson, Erik R

Committee Member(s)

• Anakk, Sayeepriyadarshini
• Kim Kemper, Jongsook
• Kranz, David M

Department of Study

Molecular & Integrative Physl

Discipline

Molecular & Integrative Physi

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

SHP

Abstract

Breast cancer remains the second cancer-related cause of death among women. With limited therapeutic options for metastatic disease, immune checkpoint blockade (ICB) was anticipated to provide a novel treatment strategy. However, the efficacy of ICB in breast cancer has been limited, in part due to the highly immunosuppressive tumor microenvironment (TME); myeloid cells and regulatory T (Treg) cells being known contributors. Nuclear receptors have been implicated in the regulation of myeloid cells. Therefore, we evaluated this superfamily, and found that higher tumoral SHP expression was associated with favorable prognosis for patients. Thus, we hypothesized that SHP modulates the TME to lower breast cancer progression. Using genetic and pharmacological approaches, we evaluated the immune and anti-cancer function of myeloid cell-expressed SHP. We found that SHP within mouse and human myeloid cells skews T cell expansion away from Tregs, resulting in more robust effector T (Teff) cell responses. Furthermore, a small-molecule agonist of SHP, DSHN, lowered Tregs in antigen-tolerized mice. Using the MMTV-PyMT model of mammary cancer, it was found that tumor growth was increased in mice lacking SHP (SHP-/-). Transcriptomic analysis of these tumors indicated an enriched suppressor T cell activity in the absence of SHP. Indeed, flow cytometry analysis indicated increased infiltration of myeloid cells and Tregs, with a concomitant decrease in Teffs. In further support for a role of myeloid cell-expressed SHP, syngeneic mammary cancer grafts grew faster in mice with SHP specifically knocked down in the myeloid lineage (LysMCre;SHPfl/fl). Importantly, treatment of mice with DSHN decreased growth of tumors and metastatic lesions in mice, highlighting the potential clinical translation of these findings. SHP expression within myeloid cells results in decreased expansion of Treg cells, ultimately altering the TME to promote immune anti-cancer activity. Our work reveals a novel mechanism to lower immunosuppression of solid cancers, which will likely enhance the efficacy of standard ICB therapy.

Graduation Semester

2020-12

Type of Resource

Thesis

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Copyright and License Information

Copyright 2020 Sayyed Hamed Shahoei

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