Date of Award
8-16-2024
Document Type
Open Access Dissertation
Department
Biological Sciences
First Advisor
Hexin Chen
Abstract
In breast cancer research, Interleukin-1 alpha (IL1α) remains a lesser-explored frontier, while its counterpart, Interleukin-1 beta, has garnered extensive scrutiny and understanding. To address this knowledge gap, our investigation leveraged the MMTVdriven HER2+ orthotopic model in Wildtype (WT) and IL1α-/- mice. Our approach demonstrated tumor regression in IL1α-/- mice at the 2-week timepoint, while WT tumors grew exponentially. At 2 weeks, IL1α-/- mice exhibited an immune "hot" microenvironment with increased CD45+ immune cells, particularly CD11b+ myeloid, and CD8+ T cells. CD8+ cells in IL1α-/- mice showed enhanced anti-tumor cytokine production and proliferative capability, with reduced inhibitory checkpoint markers like PD1. Resolving the IL1α source debate, our study identified CD11b+CX3CR1+ macrophages in the tumor microenvironment (TME) as the major contributor of IL1α using Single-Cell RNA sequencing and confirmed using flow cytometry. The absence of IL1α impacts the differentiation of CX3CR1+ macrophages in the TME, resulting in less phagocytic, more inflamed, and less immunosuppressive myeloid cells. In the TME, WT myeloid cells exhibit a human M2 macrophage gene signature, while IL1α-/- myeloid cells reflect a human inflamed monocytes/dendritic cell-like gene signature. IL1α-/- tumor regression is primarily driven by myeloid cells, with T cells playing a significant role only in clearing the tumor after the 2-week timepoint. IL1α also plays a crucial role in WT emergency hematopoiesis (EH), the absence of which stunts EH. This phenomenon can be recapitulated by IL1α neutralization antibody, while tumor growth wasn't affected significantly. These findings underscore the crucial role of IL1α both in the host and within the TME.
Rights
© 2024, Manikanda Raja Keerthi Raja
Recommended Citation
Keerthi Raja, M.(2024). Understanding the Role of Host Derived Interleukin 1 Alpha in Breast Cancer Progression. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/7851