Investigating Regulatory Mechanisms Influencing Oral Cancer-Intrinsic Type I Interferon Production and Signaling
Year: 2021
Type: dissertation
Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth-leading cause of cancer fatalities worldwide. Furthermore, a societal rise in obesity has coincided with an increased prevalence of head and neck cancers, portending potentially deleterious co-morbidities. The work outlined in this dissertation identifies novel avenues towards our understanding of how tumors mediate immune escape in both lean and obese experimental models, as well as potential limitations and considerations in developing effective immunotherapeutics. Proteins of key importance towards these efforts are type I interferons (IFN-I), characterized as potent activators of anti-tumor immunity. Indeed, this dissertation expands our mechanistic understanding of how stimulator of interferon-inducible genes (STING)-mediated IFN-I production and signaling proves to be a central mechanism in facilitating anti-tumor T-cell and myeloid cell expansions. We find that tumors from obese mouse models display increased tumor burden alongside an immunosuppressed tumor microenvironment. Palmitate, a saturated fatty acid and essential component of adipose tissue, dysregulates IFN-I production in both cancer and immune cells, leading to increased anti-tumor immune responses. Alongside this, the regulatory nucleotidebinding domain and leucine-rich repeat (NLR) protein NLRC3, which has been previously characterized as a negative regulator of IFN-I production in myeloid cells, is identified here as a negative regulator of IFN-I production within human and mouse oral cancer cells. NLRC3 expression is additionally induced in tumors derived from obesity models, indicating potential linkages between saturated fatty acids and innate immune sensors. Through assessment of the xi IFN-I-related metagene MX1, we uncovered that downstream paracrine and autocrine IFN-I signaling within oral cancer tumors is subsequently harmful to patient survival and tumor burden, by initiating events leading to the expansion of cancer stem cells. Thus, through this work, we reveal pleotropic nature of IFN-Is in modulating the tumor microenvironment. Cancer-intrinsic IFN-I production promotes pro-inflammatory anti-tumor immune activation, largely dependent on myeloid and cancer cell IFN-I production and myeloid IFN-I downstream signaling, while downstream cancer-intrinsic IFN-I signaling enacts a remodeling of the tumor microenvironment through the expansion of cancer stem cells, supporting cancer immune escape.
DOI: 10.7302/2812
Author: Heath, Blake
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4287460345