Unveiling the Mechanisms of Immune Suppression by Quiescent Cancer Cells in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature and limited targeted treatment options. New treatments are emerging with greater outcomes such as immune checkpoint blockade (ICB) which has recently been approved by the FDA (Shah et al., 2022). Clinical trials have proven that ICB can improve outcomes in TNBC patients, but the response rate is only 20%. This highlights the need to understand the mechanisms that lead to resistance to ICB in these types of cancers. Recent data (Baldominos et al., 2022) reveals that in the tumor microenvironment (TME), a subset of quiescent cancer cells are immune-invasive, resistant to immune cell killing, and possess stem cell-like properties. This thesis tries to investigate 1) the induction of these quiescent cancer cells (QCCs) in TNBC, and 2) the possible mechanism by which QCCs alter dendritic cell (DC) function. In the first part of the study, we studied the induction and characteristics of QCCs within the TNBC TME. Previous work in the lab had shown that QCCs show a hypoxia-induced gene expression signature. To address the role of hypoxia in the induction of QCCs, I utilized experimental approaches to mimic hypoxia and hypothesized that TNBC cells induce quiescence through the upregulation of HIF1a. Furthermore, we described that QCCs are highly glycolytic related to hypoxia-induced transcriptional signatures. Thus, in the second part of the study, we examined the role of cancer-immune metabolism, such as lactate, in modulating DC activation and function. Through in vitro experiments using TNBC cell lines and primary DC cultures, we hypothesized and demonstrated that lactate in the environment impairs DC activation. These findings provide valuable insights into the interplay between cancer cell metabolism and immune cell function in TNBC, with implications for immune evasion and tumor progression. This thesis aims to unveil the mechanism of QCC induction and how it shapes the immune suppressive environment through lactate-impairing DC activation and function. This study sheds light on the interactions between cancer cell metabolism, immune responses, and tumor dormancy in TNBC. These findings may help the development of novel therapeutic approaches aimed at targeting metabolic vulnerabilities and restoring immune surveillance in this aggressive subtype of breast cancer.