Abstract A017: Exploring the interplay between macrophage subtypes and colorectal cancer cell growth

Abstract

Abstract Tumor-associated macrophages, a major stromal component within the tumor microenvironment (TME), play diverse roles in tumor progression and response to therapy. Although their tumor infiltration is linked to unfavorable prognoses in various cancer types, their specific involvement in colorectal cancer (CRC) remains a subject of debate. Within the TME, macrophages can adopt pro-inflammatory (M1) or immune-suppressive (M2) phenotypes in response to signals. In this study, we aimed to investigate the intricate interplay between CRC cells and macrophages under different tumor microenvironmental stresses, shedding light on the impact of macrophage phenotype and function on tumor cell behavior. We characterized signaling pathways and macrophage markers in the THP-1 monocytic cell line, differentiating THP-1 cells into M0 macrophages and polarizing them into M1 and M2 phenotypes using distinct inducers, LPS+IFNγ or IL4+IL13, respectively. Treatment with M1 and M2 inducers resulted in the induction of p-STAT1 and p-STAT6 signaling, as well as metabolic markers like IDO and TGM2, respectively, in THP-1 cells. Subsequently, we collected conditioned media (CM) from M0, M1, and M2 macrophages and assessed their impact on colon cancer cell proliferation. Consistent with previous studies, M1 CM demonstrated a suppressive effect on the growth of several CRC cell lines, whereas M0 or M2 CM did not elicit a change. Interestingly, we found a few CRC lines where the M1 CM did not reduce cell growth, suggesting that the response to M1 macrophages may be influenced by tumor cell-intrinsic factors. To gain further insights, a high-content imaging-based workflow was utilized for physical co-cultures of macrophage subtypes and CRC cells. Furthermore, we validated our findings using patient-derived tumor organoids to examine the interaction between macrophages and CRC in a more physiologically relevant context. Overall, our systematic exploration provides valuable insights into the complex interplay between macrophage subtypes and the progression of colon cancer. It emphasizes the influence of the tumor immune microenvironment on cancer cell behavior across diverse intrinsic cellular factors. Citation Format: Chun-Te Chiang, Danielle Hixon, Nevart Mooradian, Pratiksha Kshetri, Scott Valena, Roy Lau, Charlie Ambrose, Michael Doche, Reginald Hill, Shannon M. Mumenthaler. Exploring the interplay between macrophage subtypes and colorectal cancer cell growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A017.