MAY 23, 2024 8:30 AM PDT

Immune Cell Reprogramming Suppresses Tumor Progression

Immune cells are orchestrated to elicit a comprehensive and efficacious response towards invading pathogens. The interactions between immune cells and sites of infection are complex with a multitude of proinflammatory signals. In cancer, the tumor polarizes healthy immune cells to become pro-tumorigenic. As a result, these cells suppress other immune populations and promote tumor expansion. Polarized protumor immune cells can include many different cell types including macrophages. As one of the vital cell populations in the innate immune system, macrophages normally engulf or lyse pathogens, including cancer. They help maintain tissue homeostasis and repair damage throughout the body.

In the context of cancer, macrophages can revert their function to become pro-tumorigenic by inactivating immune cells that attack the tumor. They also release different proteins to suppress other aspects of the immune response. Polarized macrophages or tumor-associated macrophages (TAMs) promote the expansion of tumor growth by mediating blood vessel formation around the tumor. This vascularization provides nutrients and an avenue to metastasize. Unfortunately, TAMs are a steep obstacle that limits therapeutic efficacy in solid tumors. Scientists are working on different ways to target these cells to not only enhance immunotherapy, but to also prolong survival in hard-to-treat cancers.

A recent article published in Cancer Immunology Research by Dr. Jelani Zarif and his team, found a way to reprogram TAMs to overcome limited therapeutic efficacy. Zarif is the Robert E. Meyerhoff Endowed Professor and an Associate Professor of Oncology at Johns Hopkins School of Medicine. His lab focuses on the molecular mechanisms in immune cells that promote tumor growth. His work also investigates new biomarkers to help predict clinical response in cancer patients.

In his recent paper, Zarif and others demonstrate how a novel therapy can reduce hard-to-treat bladder cancer. They noticed that macrophages become TAMs when grown in a dish with glutamine. Consequently, the team treated mice with JHU083, a drug that blocks glutamine from entering the cells. Interestingly, this drug does not become active and block glutamine until it enters the tumor. This type of specificity ensures that healthy tissues will not be disturbed, and toxicity is limited. Mice treated with JHU083 had significant reduction in tumor growth overall increased survival. Glutamine blockade in solid tumors led to cancer cell death, which triggered the release of proteins to kill neighboring cancer cells. JHU083 also reprogrammed TAMs to elicit an anti-tumor response. In addition to killing tumor cells directly, these reprogrammed macrophages also recruited other healthy immune cells to combat tumor progression.

Since JHU083 recruited other immune cells, the team paired the treatment with an immunotherapy referred to as immune checkpoint blockade. However, the combination treatment did not enhance further tumor regression. Zarif suggests that JHU083 could be an alternative to patients that do not respond to standard-of-care therapy.  The team plans to test this drug in clinical trials to evaluate efficacy in the clinic. Overall, Zarif and his team demonstrate solid tumor regression using a single agent compared to combination therapies which increase the risk of toxicity in patients. Their work has the potential to improve therapeutic efficacy and overall survival in resistant bladder tumors and others.

Article, Cancer Immunology Research, Jelani Zarif, Johns Hopkins School of Medicine

About the Author
Master's (MA/MS/Other)
Greetings! I am a predoctoral trainee in the Department of Immunology at Roswell Park Comprehensive Cancer Center. I am passionate about tumor immunology, and hope to one day become an independent principal investigator.
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