1385 Dynamic reciprocal interactions between activated T cells and tumor associated macrophages drive macrophage repolarization and proinflammatory T cell migration within prostate tumor models
Year: 2024
Type: conference-abstract
Abstract: Background Immune dysfunction in prostate cancer has been associated with tumor resistance to immunotherapeutics as well as poor clinical outcomes in patients. Investigation into the mechanisms that underlie immune dysfunction in prostate tumors has identified tumor-associated macrophages (TAMs) as one of the cell populations with a potent role in the inhibition of T cell recruitment and function within the prostate tumor microenvironment (TME). Methods In this study, we leveraged a novel microscale cell culture platform, known as Stacks, to perform spatio-temporal investigation of mono-, co-, and tri-culture TME models comprised of androgen-dependent and androgen-independent prostate tumor cell lines, primary macrophages, and autologous T cells from patients with prostate cancer. We have performed multiplexed analysis of mRNA, surface and secreted protein expression, and cell migration within these prostate tumor models. Results We have captured a dynamic interaction between TAMs and activated T cells that resulted in reciprocal proinflammatory activation of both cell populations upon interaction in the context of prostate tumor cells. The presence of TAMs in our TME models promoted a 3–4 fold increase in tumor-directed migration in both the CD4 and CD8 subsets. Additionally, TAMs induced proinflammatory skewing of T cells including an increase in CXCR3, a decrease in CCR4 expression and enhanced TNF-alpha secretion. In return, activated T cells re-programmed TAM towards a pro-inflammatory profile independent of their pre-polarized M1/M2/M0 states captured in increased CXCL9, CXCL10 and CXCL11 mRNA expression and elevated CD86 surface expression. Additionally, we found that the T cell-mediated TAM reprogramming was abrogated by IFN-gamma neutralization. Conclusions Our novel model system represents a first-in-kind, integrated in vitro analysis of the multi-cellular prostate tumor immune microenvironment. Our findings suggest that activated T cells are capable of re-polarizing immunosuppressive TAMs in the context of prostate tumor networks and that TAM re-polarization may play a key supportive role in restoring proinflammatory T cell tumor responses in the prostate TME. These findings provide a targetable mechanism to enhance anti-tumor immune responses. Acknowledgements We thank the UWCCC Optical Imaging Core Facility for use of shared equipment and excellent technical support. This work was supported by the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program, Award No. W81XWH-18-1-0273 to DK. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This work was also supported by the shared resources grant ‘University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520’ by the National Institutes of Health including support for facilities and core services at the UWCCC Flow Cytometry Lab, Small Molecule Screening Facility, and the Translational Science Biocore. Ethics Approval Blood samples were collected from patient donors with prostate cancer after receiving written informed consent under a protocol approved by the Institutional Review Boards at the University of Wisconsin-Madison (#2014-1214) and at the William S Middleton Memorial Veteran’s Hospital, Madison, WI (#WI-018). Research has been performed in accordance with the Declaration of Helsinki.
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4404064718