New Immunotherapy Targets Immune Shield Around Tumors, Boosting Cancer Cell Elimination
For decades, the field of oncology has witnessed remarkable advancements with the advent of cancer immunotherapy. This transformative approach harnesses the body’s own immune system to identify and eliminate cancerous cells. Strategies such as immune checkpoint inhibitors and engineered immune cells, particularly CAR-T cell therapies in blood cancers, have yielded durable responses in many patients. Several CAR-T treatments are now approved by regulatory agencies and have demonstrated long-term remissions in leukemia and lymphoma.
However, replicating this success in solid tumors has proven significantly more challenging. Unlike blood cancers, solid tumors often cultivate a hostile microenvironment that actively suppresses immune responses. Engineered T cells frequently struggle to penetrate tumors, persist long enough to exert their effects, or maintain functionality once inside. Consequently, researchers are increasingly shifting their focus from directly targeting cancer cells to modulating the immune ecosystem that surrounds and protects them.
A groundbreaking study recently published in the journal Cancer Cell details an experimental immunotherapy that targets tumor-associated macrophages (TAMs) rather than the cancer cells themselves. This innovative approach aims to dismantle the immune shield that allows tumors to evade immune attack. As one of the study’s lead authors noted, “What we call a tumor is really cancer cells surrounded by cells that feed and protect them. It’s a walled fortress.”
Macrophages are among the most abundant immune cells within solid tumors, often comprising up to 50 percent of the immune cell population in the tumor microenvironment (TME). While macrophages typically serve as the first responders to infection and tissue damage, tumors manipulate them, reprogramming these cells to suppress immune activity and promote tumor growth and metastasis. The research team hypothesized that eliminating these protective macrophages would enable the body’s own killer T cells to effectively eliminate cancer cells.
A key advantage of targeting macrophages over cancer cells lies in the fact that cancer cells often do not express many molecules distinct from the cells they originate from. This raises the risk of inadvertently harming healthy cells that also express the same molecules. In contrast, years of tumor profiling have revealed that TAMs exhibit upregulated specific markers, including FOLR2 (folate receptor 2) and TREM2 (triggering receptor expressed on myeloid cells 2), which are far less common on normal macrophages.
The researchers devised a strategy to generate CAR T cells that specifically target these markers, effectively using the CAR T cells as a “Trojan horse” to infiltrate the tumor. While previous attempts using macrophage-targeting CAR T cells have shown promise in preclinical models, their effects have often been short-lived, with tumors eventually rebounding. To address this, the Mount Sinai team built upon earlier findings indicating that interferon gamma (IFNγ) release is crucial for anti-macrophage CAR T cell activity. They engineered CAR T cells to not only target TAMs expressing FOLR2 or TREM2 but also to secrete IL-12 (interleukin-12), a potent immune-activating cytokine.
This approach enhances the durability of the therapy by ensuring that replacement macrophages become immunostimulatory rather than immunosuppressive, creating a self-sustaining reprogramming of the tumor microenvironment. To understand the intricate changes occurring within the tumors, the researchers employed spatial transcriptomics, alongside flow cytometry and multiplex imaging techniques.
The results were striking. After 10 days of treatment, tumors exhibited a dramatically altered immune architecture. Instead of macrophages expressing immunosuppressive molecules, they displayed a surge in immunostimulatory and anti-cancer molecules such as MHC class I, CD40, TNF, and CYBB. Simultaneously, the number of cytotoxic CD8+ T cells, the primary immune cells responsible for killing cancer cells, more than tripled. These immune changes translated into remarkable outcomes in preclinical models, with mice bearing metastatic lung and ovarian cancers surviving for months longer, and many being completely cured.
One of the most compelling aspects of this strategy is its potential applicability across a wide range of cancer types. By targeting the immune cells that surround and protect tumors, rather than directly attacking cancer cells, the therapy could be effective even in cancers that lack readily identifiable tumor antigens. The researchers found that when the surviving mice were rechallenged with cancer cells, their immune system immediately eliminated the cancer, a hallmark of robust immune memory.
The team is currently focused on refining the approach, particularly by controlling the precise location and manner in which IL-12 is released within tumors to maximize effectiveness while ensuring safety. Beyond lung and ovarian cancer, the researchers believe this strategy could serve as a foundation for future CAR T therapies designed to reshape tumors by targeting their support cells rather than the cancer cells themselves.
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