Posted on February 28, 2025 | Jose Ramon Conejo-Garcia,MD, PHD – Duke Cancer Institute
Cancer immunotherapy has long been dominated by T cells and immune checkpoint inhibitors. However, a groundbreaking presentation by Jose Ramon Conejo-Garcia, MD, PhD, from Duke Cancer Institute, is shifting the spotlight to an overlooked player: humoral immunity. In a recent talk, Dr. Conejo-Garcia shared how isotype-switched antibodies produced in tertiary lymphoid structures (TLS) could hold the key to antagonizing human cancer progression. This offers new hope for more effective treatments. Here’s what you need to know about this exciting frontier in cancer research.
The Power of Humoral Immunity in Cancer
For years, the field of cancer immunotherapy has focused on T cells—those immune heavyweights activated by drugs like checkpoint inhibitors or engineered through CAR-T therapies. But Dr. Conejo-Garcia’s lab at Duke is digging deeper. They are exploring how B cells and the antibodies they produce can complement these approaches. His team is particularly interested in tertiary lymphoid structures (TLS), which are clusters of T and B cells that form within tumors and mimic the architecture of lymph nodes. These structures, it turns out, are more than just bystanders—they’re active players in the fight against cancer.
What Are Tertiary Lymphoid Structures (TLS)?
TLS are like mini immune hubs that pop up inside tumors. Dr. Conejo-Garcia explained that they’re consistently linked to better patient outcomes, including stronger responses to immunotherapy. But why? One theory is that TLS act as a protective niche, shielding T cells from the tumor’s immunosuppressive environment. Another is that B cells within TLS serve as antigen-presenting cells, keeping T cells primed and ready. Most intriguingly, TLS house germinal centers where antibodies are born—antibodies that could directly attack cancer cells.
A Breakthrough Discovery: Tumor-Fighting Antibodies
Using cutting-edge techniques like laser capture microdissection and PCR amplification, Dr. Conejo-Garcia’s team zoomed in on the antibodies produced in TLS. In ovarian cancer samples, they found highly clonal responses—up to 75% of B-cell receptors stemmed from a single clone. From there, they cloned and produced a recombinant IgA antibody that targets a tumor-promoting growth receptor. Lab tests showed it could inhibit the growth of the patient’s own tumor, proving TLS-derived antibodies aren’t just theoretical—they’re functional. Notably, TLS produce a mix of IgA (50%) and IgG (50%) antibodies. IgA shows promise in penetrating mucosal tumors.
Inducing TLS: A New Therapeutic Avenue
Could we deliberately trigger TLS formation to boost cancer immunity? Dr. Conejo-Garcia’s collaboration with Roger Lee at Morphic suggests yes. By injecting an oncolytic virus into cancer patients, they observed remarkable TLS formation alongside clinical responses. These TLS-generated antibodies targeted both the virus and the tumor, hinting at a dual-purpose strategy that could amplify immunotherapy’s impact.
Targeting Hidden Tumor Markers
In another collaboration with Scott Antonia at Duke, the team uncovered an antibody from TLS that zeroes in on citrullinated proteins. This is a process where arginine turns into citrulline, exposing intracellular proteins on tumor cell surfaces. Found in non-small cell lung cancer, this discovery opens doors to targeting not just tumor cells but also the surrounding microenvironment. This includes myeloid cells and fibroblasts. The team is now developing a CAR (chimeric antigen receptor) platform based on this finding, expanding the arsenal of immunotherapy tools.
The Future of TLS-Based Immunotherapy
Dr. Conejo-Garcia’s work is a conceptual leap forward. By harnessing TLS-derived antibodies, researchers could enhance existing treatments like checkpoint inhibitors and CAR-T therapies, tailoring solutions to individual patients. The next steps? Understanding the cellular dynamics within TLS and scaling these discoveries into clinical applications. With ongoing collaborations and innovative platforms, the future looks bright for this immunotherapy revolution.
Keywords: Immunotherapy, Cancer Research, TLS, Antibodies, Duke Cancer Institute, Cancer Treatment, Humoral Immunity, Oncolytic Virus, CAR Therapy, Medical Science
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