In experiments with mouse models of breast, pancreatic, and muscle cancers, researchers at Johns Hopkins All Children's Hospital report new evidence that a novel means of boosting the natural immune system prevents cancer recurrence and improves survival.
The study, published Sept. 2 in Nature Immunology, was federally funded by the National Cancer Institute/NIH.
Malignant tumors are often described as immune-suppressive or "immune cold," meaning the patient's immune system does not recognize or attack the tumors. Patients with these tumors typically respond poorly to conventional therapies and face worse prognoses. This study explores how to convert immune-cold tumors into immune-responsive or "immune hot" tumors, enabling immune cells such as B cells and T cells to attack cancer cells more effectively and enhance the success of chemotherapy and immunotherapy.
Building on their earlier research in breast cancer, the research team hypothesized that "spicing up" the tumor environment with immune activating agents improves the "fitness" of tertiary lymphoid structures (TLSs) and dramatically enhances immune responses to target tumors.
TLS are clusters of lymphocytes that form in areas of chronic inflammation, including immune-hot tumors. These structures are critical in helping the immune system fight cancer, and their presence strongly correlates with improved treatment responses and patient survival.
To test their approach, the researchers "reverse-engineered" a TLS-rich tumor environment to identify the stimuli required for TLS formation. They then applied these stimuli to TLS-free tumors growing in mice, administering two immune-activating substances (agonists) that stimulate the protein STING and the lymphotoxin-β receptor (LTβR).
Dual activation of STING and LTβR triggered a rapid response from killer T cells (CD8⁺ T cells), leading to strong tumor growth inhibition. The treatment also induced the formation of high endothelial venules, the specialized blood vessels that admit lymphocytes into tissues. These blood vessels functioned like dedicated gateways, enabling large numbers of T and B cells to enter the tumors and assemble into TLSs.
Within these TLS, B cells initiated germinal‑center reactions, matured into antibody‑secreting plasma cells, and generated long‑lived memory cells. Tumor‑specific IgG antibodies were detected, and plasma cells persisted in the bone marrow—evidence of durable, systemic immunity that can help protect against relapse.
Treatment also increased helper (CD4⁺) T cells and memory CD8⁺ T cells and balanced immune signaling, strengthening both antibody‑mediated (humoral) and cell‑mediated immunity.
Together, the researchers say, the findings suggest early and combined efforts to boost T‑cell activity not only kill tumor cells directly but also induce TLS maturation that sustains and amplifies anti-tumor responses.
"Our findings show that we can therapeutically induce functional TLS in otherwise immune‑cold tumors," says Masanobu Komatsu, Ph.D., principal investigator of the study and senior scientist at the Johns Hopkins All Children's Cancer & Blood Disorders Institute. "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."
Because TLS abundance correlates with better outcomes across many tumor types, the use of the two protein stimulators together may offer a broadly applicable way to enhance the effectiveness of existing therapies, including checkpoint inhibitors that are the mainstay of immunotherapies, and traditional chemotherapy.
Komatsu's team is further investigating the mechanism of action of TLS therapy and preparing for its clinical application in adult and pediatric cancer patients.
This research was supported by the National Cancer Institute/NIH R01 grants, the Department of Defense Congressionally Directed Cancer Research Program, and the Florida Department of Health Bankhead Coley Cancer Research Program.
One of the co-authors of the study has potential competing interests.
