They have found the key that makes the body attack cancer

Research recently published in Nature Immunology With funding from the National Cancer Institute/National Institutes of Health, he focused on finding new ways to help the immune system recognize and destroy tumors that would normally evade detection.

Many malignancies are described as immunosuppressive or “immune cold” because the body’s defenses fail to recognize them as threats. Patients with these “cold” tumors often respond poorly to conventional treatments and have less favorable outcomes. The Johns Hopkins team set out to discover how to turn these immune-cold tumors into “immune-hot” tumors, which are more responsive to attack by immune cells such as B cells and T cells. Doing so may make chemotherapy and immunotherapy much more effective.

Based on their previous studies in breast cancer, the researchers proposed that stimulating the tumor environment with immunostimulating substances could improve the strength and organization of tertiary lymphoid structures (TLSs), specialized hubs where immune cells congregate and coordinate the attack against cancer.

TLSs are clusters of lymphocytes that appear in areas of chronic inflammation, including hotspot immune tumors. Their presence is strongly associated with better treatment outcomes and longer survival because they help coordinate a focused immune response.

To test their idea, the team recreated the conditions of a TLS-rich tumor environment to identify the signals that trigger TLS formation. They then introduced these signals into tumors in mice lacking TLSs, using two immune-stimulating molecules (agonists) designed to activate the protein STING and the lymphotoxin beta receptor (LTβR).

When both proteins were activated together, the immune system mounts a rapid and strong response. Killer T cells (CD8⁺ T cells) sprang into action, suppressing tumor growth, while new superior endothelial venules – specialized blood vessels that allow immune cells to enter tissues – began to form. These vessels acted as gateways, enabling large numbers of T and B cells to flow into tumors and organize themselves into new TLSs.

Within these TLSs, B cells initiated germinal center reactions, developed into antibody-producing plasma cells, and generated long-term memory cells. The researchers also found tumor-specific IgG antibodies and persistent plasma cells in the bone marrow, clear signs of an enduring immune defense throughout the body capable of preventing cancer from coming back.

The treatment also resulted in increased helper T cells (CD4⁺) and memory CD8⁺ T cells and balanced immune signaling, enhancing both antibody-mediated (humoral) and cell-mediated immunity.

The findings point to early, collaborative efforts to enhance T-cell activity not only to directly kill cancer cells but also to induce TLS maturation that sustains and amplifies anti-tumor responses, the researchers say.

“Our findings show that we can therapeutically induce functional TLS in cold immune tumors,” says Dr. Masanobu Komatsu, the study’s lead researcher and senior scientist at the Johns Hopkins Children’s Cancer and Blood Disorders Institute. “By building the right immune infrastructure within tumors, we can boost the patient’s own defenses – both T cells and B cells – against cancer growth, relapse and spread.”

Because TLS abundance is associated with better outcomes across many tumor types, using the two protein coactivators together may provide a broadly applicable approach to enhance the efficacy of current therapies, including checkpoint inhibitors that are the mainstay of immunotherapies, and conventional chemotherapy.

The Komatsu team is further investigating the mechanism of action of the TLS treatment and preparing for its clinical application in adult and pediatric cancer patients.

This research was supported by National Cancer Institute/NIH R01 grants, the Department of Defense Congressionally Directed Cancer Research Program, and the Florida Department of Health Bankhead-Colley Cancer Research Program.

One of the study’s co-authors has potential competing interests.