Reprogramming the Immune System: Johns Hopkins Researchers Discover a Way to Turn “Cold” Tumors “Hot”
Cancer remains one of humanity’s most formidable adversaries, in part because of its ability to hide in plain sight. While advances in immunotherapy have revolutionized cancer treatment, many malignant tumors remain resistant to these therapies because they are “immune cold”—meaning the body’s immune system fails to recognize them as threats. In a landmark study published in Nature Immunology, scientists at Johns Hopkins All Children’s Hospital have revealed a groundbreaking approach that could change that. By reprogramming the tumor’s environment and strengthening the body’s natural immune defenses, they found a way to convert these immune-cold tumors into “immune hot” ones—making them far more vulnerable to attack and destruction.
This new line of research, supported by the National Cancer Institute (NCI/NIH), the Department of Defense Congressionally Directed Cancer Research Program, and the Florida Department of Health Bankhead Coley Cancer Research Program, offers fresh hope that cancers previously resistant to treatment could become highly responsive to both traditional therapies like chemotherapy and cutting-edge immunotherapies.
Understanding the Challenge: Immune Cold vs. Immune Hot Tumors
The immune system is designed to detect and eliminate abnormal cells before they form dangerous tumors. However, certain cancers evade detection by creating an immunosuppressive environment that effectively hides them from immune surveillance. These “immune-cold” tumors lack sufficient infiltration of immune cells, particularly B cells and T cells, which are vital for orchestrating a targeted response against cancer. As a result, patients with immune-cold tumors often experience poor responses to therapy and worse survival outcomes.
Conversely, “immune-hot” tumors are rich in immune cell infiltration and inflammation. They attract active immune components and feature specialized microstructures called tertiary lymphoid structures (TLSs)—clusters of lymphocytes that organize within the tumor environment to coordinate the immune attack. Studies have shown that the presence of TLSs correlates strongly with better prognosis and higher survival rates. Recognizing this, the Johns Hopkins team aimed to uncover a method to induce TLS formation in immune-cold tumors, thereby transforming them into immune-active zones capable of resisting cancer growth and recurrence.
The Johns Hopkins Breakthrough: Engineering an Immune-Active Tumor Microenvironment
Building upon earlier breast cancer studies, Dr. Masanobu Komatsu and his colleagues at the Johns Hopkins All Children’s Cancer & Blood Disorders Institute sought to determine whether it was possible to create TLSs within immune-cold tumors through targeted immune stimulation. Their hypothesis was straightforward yet ambitious: if the right immune signals could be introduced into the tumor microenvironment, perhaps they could trigger TLS formation and activate both the T-cell and B-cell arms of the immune system.
To test this, the researchers used mouse models of breast, pancreatic, and muscle cancers—three tumor types known for their resistance to immune-based therapies. They recreated conditions resembling TLS-rich environments to identify the molecular signals responsible for TLS formation. This led them to two key immune-stimulating molecules, or agonists, that activate critical pathways in the immune system: the STING (Stimulator of Interferon Genes) protein and the lymphotoxin-β receptor (LTβR).
When the team simultaneously activated both pathways in tumor-bearing mice, they observed a dramatic transformation. The immune system mounted a powerful and coordinated response. CD8⁺ cytotoxic T cells, often referred to as “killer” T cells, surged into action, attacking and suppressing tumor growth. Meanwhile, specialized blood vessels known as high endothelial venules (HEVs) began to form within the tumors. These vessels act as crucial gateways, allowing immune cells to efficiently enter the tumor tissue and organize into new TLSs.
Formation and Function of Tertiary Lymphoid Structures
Inside these newly formed TLSs, B cells began to proliferate and mature through germinal center reactions, a process by which they refine their ability to recognize and bind to cancer-specific antigens. From these germinal centers emerged antibody-producing plasma cells and memory B cells capable of providing long-term immunity. The presence of tumor-specific IgG antibodies and persistent plasma cells in the bone marrow demonstrated that the induced immune response was not only strong but also enduring—offering the potential to prevent cancer relapse even after initial treatment.
In addition to B-cell activation, the researchers noted a significant rise in helper (CD4⁺) T cells and memory (CD8⁺) T cells. These cells play a central role in sustaining immune responses over time, ensuring that if the cancer were to reappear, the immune system could rapidly recognize and destroy it. The treatment also achieved a balanced activation of both humoral immunity (antibody-mediated) and cell-mediated immunity, creating a comprehensive and multifaceted defense against cancer.
Dr. Komatsu summarized the significance of this dual activation succinctly:
“Our findings show that we can therapeutically induce functional TLS in otherwise immune-cold tumors. By building the right immune infrastructure inside tumors, we can potentiate the patient’s own defenses—both T cell and B cell arms—against cancer growth, relapse, and metastasis.”
Why TLS Induction Matters for Cancer Therapy
The implications of this study are profound. Many immunotherapies, such as checkpoint inhibitors, rely on the presence of active immune cells within tumors to work effectively. However, in immune-cold cancers, the lack of such cells makes these treatments less effective. By artificially inducing TLS formation, Komatsu’s team demonstrated a way to prime the tumor environment for successful immunotherapy.
This strategy could also complement conventional treatments like chemotherapy, which sometimes damages immune cells as it targets cancer. If TLS formation can be maintained or enhanced alongside chemotherapy, it could amplify the immune response and lead to more complete tumor eradication. Because TLS abundance correlates with improved outcomes across multiple cancer types—including breast, pancreatic, melanoma, and lung cancers—the Johns Hopkins approach may have broad clinical applications.
Moreover, the study highlights how manipulating the tumor microenvironment (TME)—once viewed merely as a passive background—can play an active and decisive role in determining therapeutic success. The creation of a supportive immune ecosystem inside the tumor effectively transforms it from a sanctuary for cancer cells into a battlefield where the immune system has the upper hand.
Future Directions: From Mouse Models to Human Patients
While the results from mouse models are exceptionally promising, translating them into human therapies will require rigorous testing and refinement. Dr. Komatsu’s team is now investigating the precise mechanisms of TLS induction—how the STING and LTβR pathways interact, how long the TLS structures persist, and how they communicate with other immune components across the body.
The researchers are preparing for clinical applications of TLS-based therapy in both adult and pediatric patients. They are also exploring how TLS induction could synergize with checkpoint inhibitors, cancer vaccines, and CAR-T cell therapies to create long-lasting and systemic immunity against a wide range of cancers.
It is worth noting that one of the study’s co-authors has disclosed potential competing interests, underscoring the need for transparency and careful validation as the research progresses toward human trials.
Conclusion: A Paradigm Shift in Cancer Immunotherapy
The Johns Hopkins study marks a pivotal moment in the evolution of cancer immunotherapy. By uncovering a method to convert immune-cold tumors into immune-hot ones, researchers have not only provided a strategy for improving existing treatments but also opened the door to new avenues of durable cancer prevention.
The induction of tertiary lymphoid structures within tumors represents more than just a technical achievement—it reflects a deeper understanding of how the immune system can be guided, trained, and empowered to fight back. As scientists continue to decode the interplay between cancer and immunity, this discovery stands as a testament to the promise of immune engineering: a future where the body itself becomes the most potent weapon against disease.
Story Source: Johns Hopkins Medicine
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