The Role of the NLRP3 Inflammasome in the Response to Anti-PD-1 Therapy in Metastatic Breast Cancers

May, Makenna Joy

Undergraduate Honors Thesis

The Role of the NLRP3 Inflammasome in the Response to Anti-PD-1 Therapy in Metastatic Breast Cancers Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/undergraduate_honors_theses/2j62s6254

Abstract

The Interleukin 1 (IL-1) family of cytokines is a diverse class of secreted and membrane bound messenger proteins. The IL-1 family includes the exceptionally important proinflammatory cytokine IL-1β. IL-1β release is dependent on the nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing 3 (NLRP3) inflammasome expressed in cells of the myeloid lineage. The NLRP3 inflammasome cleaves inactive pro-IL-1β into its active, secreted form (Latz, Xiao, & Stutz, 2013). In advanced metastatic breast cancer, there is a high expression of IL-1β as a result of the substantial activation of infiltrating and resident myeloid cells within the tumor microenvironment (TME) (Wu et al., 2018), (Bergenfelz et al., 2020), (Jang et al., 2020). These infiltrating myeloid cells can participate in immunosuppression by the upregulation of T cell inhibitor programmed cell death ligand (PD-L1). This immunosuppression is exasperated by the TME, and tumor cells can express PD-L1 to evade T cell toxicity. For these reasons, we investigated the role of the NLRP3 mechanism of IL-1β release in relation to breast cancer with a clinically tested cancer treatment, anti-PD-1 therapy☨. We observed that human myeloid cells, stimulated with conditioned media from triple-negative breast cancer MDA-MB-468 cells led to NLRP3 activation and increased gene expression of PD-L1. In vivo, mice lacking NLRP3 and implanted with the metastatic breast cancer cell line E0771 showed a significant reduction in tumor growth (p < 0.05) and improved survival (p < 0.01). Using OLT1177®, an NLRP3 inhibitor, we showed reduced gene expression of PD-L1 (p < 0.001), caspase-1, the protein responsible for cleaving and activating IL-1β in the NLRP3 inflammasome (p < 0.01), and IL-1β (p < 0.01) in primary tumors. Combining NLRP3 inhibition with anti-PD-1 treatment significantly reduced tumor growth compared to monotherapies (p < 0.05). We show inhibition of NLRP3 accompanied by anti-PD-1 therapy yields a promising treatment for metastatic breast cancers.

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