Abstract Introduction: Grape seed procyanidin extract (GSE) and milk thistle silymarin extract (MTE) are widely used as health food supplements to promote cardiovascular and hepatobiliary health, respectively. Both GSE and MTE contain high levels of structurally distinct polyphenols and each agent has been shown to exert antineoplastic effects against lung cancer. Previously we have shown that the combinations of GSE and MTE decreased production of the tumor promoting, M2 macrophage polarizing CCL2 chemokine by lung cancer cells. CCL2 is a key chemokine in the tumor microenvironment that facilitates recruitment and polarization of macrophages toward the tumor promoting M2c phenotype, which promotes tumor progression by creating a pro-tumorigenic environment. Targeting recruitment to and M2c macrophage polarization in the lung tumor microenvironment with GSE + MTE may represent a novel immunotherapeutic strategy against lung cancer. Methods: THP-1 cells were differentiated into M0 cells with phorbol-12-myristate-13-acetate (PMA), then to M2c macrophages using interleukin (IL)-10 priming as previously described. M2c phenotype was then confirmed using qPCR profiling with CD163 and CD206 primers. The effects of GSE and MTE conditioning, alone or in combination, on the ability of A549 cells to recruit M2c cells were assessed using co-culture migration/invasion assay of THP-1 derived M0 and M2c macrophages with A549 cells and conditioned cell culture supernatants, simulating the lung tumor microenvironment. Results: Conditioning of A549 cells with GSE and MTE additively reduced CCL2 production by A549 cells and co-culture with GSE + MTE conditioned A549 cells/supernatants additively decreased migration/invasion of M2c cells. Conclusions: In the present study, we report on the additive effects of GSE and MTE on reducing the migration/invasion of tumor promoting M2c cells in the lung tumor microenvironment. Our findings illustrate a potential novel immunomodulatory mechanism of GSE combined with MTE against lung cancer and support the continued investigation of the combinations for lung cancer prevention and treatment. Citation Format: Jenny T. Mao, Diego Oliva, Jessica Schilter, Lauren Rollin, Lily Jih, . Combinations of grape seed procyanidin extract and milk thistle silymarin extract additively decrease recruitment of THP-1 derived M2 macrophages into the lung tumor microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7475.
Mao et al. (Fri,) studied this question.