Abstract 176: Stearic acid induces pro-inflammatory macrophage response important for lung cancer development

Abstract

Abstract Background Survival is improved with early detection and treatment initiation in patients with lung cancer (LC) emphasizing the importance of tumor initiation and biomarker development in individuals at high risk for developing LC and those with early-stage LC. Recent studies suggest that immunologic and metabolic changes within the microenvironment are pivotal for tumor formation. We recently demonstrated that in patients with resectable, early-stage LC, elevated levels of stearic acid (SA), a long chain fatty acid, and macrophage inflammatory protein 1β (MIP-1β/CCL4) were predictive of tumor affected lung lobes. Therefore, we hypothesize that SA promotes LC initiation through the activation of macrophages (MΦ) and production of proinflammatory cytokines like CCL4. Methods and Results: We performed untargeted metabolomics utilizing LC-MS from the plasma of patients with various stages of LC and found elevated levels of SA in patients with early-stage LC. To further study the mechanistic role of SA in tumorigenesis, cell lines including immortalized lung epithelial, LC cells, and immune (MΦ and T) cells were treated with SA. We found that physiological concentrations of SA did not affect cellular viability. However, in MΦ, SA induced expression of inflammatory (IL6, iNOS), and immunomodulatory (Arg1, CD206) genes suggesting a role for SA in promoting a pro-tumorigenic immunologic state. Additionally, analysis of the secretome from SA stimulated MΦ using single cell proteomic analysis (Isolight, Bruker Cellular Analysis, Inc), indicated a significant enrichment of polyfunctional MΦs with enhanced secretion of enriched effector and stimulatory cytokines. Furthermore, conditioned media derived from SA stimulated MΦ led to increased proliferation, as well as anchorage independent growth, of BEAS2B immortalized lung epithelial cells. Conclusion: Our data demonstrates plasma levels of SA are increased in early-stage compared to late-stage patients with LC. This observation corresponds to our prior data demonstrating enrichment of SA in the tumor affected lobes of patients with early-stage LC. Recent studies demonstrating the induction of inflammatory responses through MΦ activation in obese patients by circulating SA in blood corroborates our observations as well. Our data suggests that the SA effect on MΦ, is critical in LC initiation not only increasing proliferation but also induction of neoplastic transformation of immortalized lung epithelial cells. Furthermore, our data indicates that blood plasma levels of SA, a fatty acid understudied in tumor biology, could also be exploited as a potential biomarker for LC development in individuals at high-risk for LC development as well as those patients with early-stage disease. Citation Format: Amrita Roy, Martin Davis, Samuel Weinberg, Apurva Mallisetty, Alicia Hulbert, Frank D. Weinberg. Stearic acid induces pro-inflammatory macrophage response important for lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 176.