Researchers have discovered a fascinating interplay between immune cells in prostate tumors. Tumor-associated macrophages (TAMs) are known to suppress the anti-tumor activity of T cells in prostate cancer. However, this new study shows that when activated T cells interact with TAMs, they can actually reprogram the macrophages to become more pro-inflammatory and support T cell migration into the tumor. This dynamic, reciprocal relationship between T cells and TAMs could be an important target for future prostate cancer immunotherapies.
Prostate Tumors: A Challenging Microenvironment for Immune Cells
Prostate cancer has been notoriously difficult to treat with immunotherapies – drugs that harness the body’s own immune system to fight cancer. While immunotherapies have shown remarkable success against some cancers, they have had limited benefit for patients with prostate tumors. Researchers have long puzzled over why the prostate tumor microenvironment (TME) is so resistant to immune attack.
One key factor appears to be the presence of tumor-associated macrophages (TAMs). These immune cells, which are derived from monocytes, tend to adopt an immunosuppressive “M2-like” phenotype within prostate tumors. TAMs can block the ability of T cells – the immune cells that normally seek out and destroy cancer cells – from infiltrating and attacking the tumor.
Harnessing the Dynamic Interplay Between T Cells and TAMs
In this new study, researchers set out to better understand the complex relationship between TAMs and T cells in the prostate TME. Using a novel microfluidic cell culture platform called “Stacks”, they were able to create realistic 3D models of the prostate TME by combining tumor cells, macrophages, and T cells isolated from prostate cancer patients.
Surprisingly, the researchers found that when activated T cells were introduced into these TME models, they were able to “reprogram” the TAMs to become more pro-inflammatory and supportive of T cell migration into the tumor. Specifically, the activated T cells induced TAMs to increase their secretion of important chemokines like CXCL9, CXCL10, and CXCL11, which help attract T cells into the tumor.
A Reciprocal, Feedback Loop Between T Cells and TAMs
The relationship between the T cells and TAMs in this study was highly dynamic and reciprocal. Not only did the T cells reshape the TAM phenotype, but the reprogrammed TAMs also helped to further activate the T cells, creating a self-reinforcing feedback loop.
The researchers found that the T cell-mediated reprogramming of the TAMs was largely dependent on the T cells’ secretion of interferon-gamma (IFN-γ). When they blocked IFN-γ, they were able to prevent the TAMs from upregulating their pro-inflammatory factors.
These findings suggest that even in the notoriously immunosuppressive prostate TME, there is the potential to “reawaken” the anti-tumor capabilities of T cells by targeting the dynamic interaction between T cells and TAMs. Future immunotherapies that can tip this balance in favor of a more pro-inflammatory TME may be key to improving outcomes for prostate cancer patients.
Author credit: This article is based on research by Erika Heninger, Matthew Thomas Breneman, Emma Elizabeth Recchia, Sheena Catherine Kerr, Reyna Elvan Dogru, Marina Nasrin Sharifi, Aaron Matthew LeBeau, David Kosoff.
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