Abstract 1347: PAUF stimulates monocytes and induces their differentiation into tumor-associated macrophages

Abstract Background: One of the main reasons for the failure of cancer treatments is that the biological function of therapeutic target molecules is only studied in cancer cells. Therefore, the dynamic and complex interactions between cancer and stromal cells in the tumor microenvironment (TME) should be investigated. TME-specific stromal cells include various cells, with tumor-associated macrophages (TAMs) being one of the major players. TAM are differentiated from monocytes, as immature monocytes recognize molecules derived from infected cells or foreign substances, become activated, and may differentiate into anti-tumoral M1 macrophages or pro-tumoral M2 macrophages (called TAMs). TAMs induce immune evasion of cancer cells in the TME, leading to active proliferation and metastasis of cancer cells. The presence of TAMs in the TME is associated with poor prognosis in various cancers. PAUF is a protein that is secreted by cancer cells, and it exerts tumor-promoting effects through autocrine and paracrine mechanisms. Compared to the autocrine actions, the paracrine effects of PAUF on immune cells in the TME are less understood. Objective: This study aimed to evaluate 1) the role of PAUF as a TME modulator, and specifically, a TAM inducer and 2) the potentiality of PAUF antibody as a blocker of TAM transformation. Methods and Results: In a monocyte-PAUF co-culture system, PAUF (tested at two concentrations, 0.1 and 0.5 μg/mL) demonstrated strong chemoattractant effects on monocytes (~400% of that caused by PBS), which were blocked by TLR2/4 inhibitors. PAUF also induced differentiation of monocytes into macrophages, which were identified to be TAM, using flow cytometric analysis and ELISA method. Moreover, these PAUF-induced TAM demonstrated T cell suppressing capacities. Finally, in a CFPAC-1 human cancer orthotopic mouse model, a humanized monoclonal PAUF-antibody diminished 60-70% of infiltrated TAM (p<0.01), quantified using an immunofluorescence assay (IFA). Conclusion: In conclusion, this study provides direct evidence that PAUF can differentiate monocytes into TAM of immune-suppressing functions, and the PAUF neutralization-induced TAM infiltration blocking suggests potential combination use of PAUF antibody with immunotherapeutics for cancer treatments. Citation Format: Fen Jiang, Yeon Jeong Kim, Yun Yong Park, Tae Heung Kang, Sang Seok Koh. PAUF stimulates monocytes and induces their differentiation into tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1347.