A newly identified stage of lymph node-like structure seen in liver tumors after pre-surgical immunotherapy may be vital for successfully treating patients with hepatocellular carcinoma, according to a study by researchers. Johns Hopkins Kimmel Cancer Center.

Study published on October 25 Nature ImmunologyIt provides new information about lymph node-like structures called tertiary lymphoid structures. These structures, where immune B and T cells cluster in a highly organized manner, are found in some patients treated with immune checkpoint inhibitors (substances that reactivate the body’s natural anti-cancer immunity) and are associated with greater treatment response. But researchers are still trying to understand exactly how these structures contribute to immune responses to cancer, how they change over time, and what finding them in tumors means for patients.

The study identifies a previously unknown form of these structures. Researchers found that patients with more of these structures were less likely to have their cancer return after surgery.

“We have identified the life cycle of tertiary lymphoid structures in patients with liver cancer, and our conclusion is that these structures may be crucial in the generation of anti-tumor immunity and may increase the likelihood of curing cancer,” he says. Mark Yarchoan, MDDr., an associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

Yarchoan and colleagues previously first clinical trials Immunotherapy before hepatocellular carcinoma surgery. Only a fraction of patients have been cured with this approach, and researchers are trying to understand why.

“One of the things that struck us when we looked at these tumors was that patients who responded to immunotherapy had tertiary lymphoid structures,” he says. Structures such as lymph nodes contain infection-fighting immune B cells in the middle, and tumor-killing immune T cells on the outside. “We wanted to find out what these structures were doing.”

They found that tumors with more tertiary lymphoid structures shrank more after immunotherapy and were less likely to reoccur after surgical removal. Tumors without these structures, on the contrary, did not shrink and were more likely to reappear after surgery. Tertiary lymphoid structures growing at the center of tumors rather than at their edges were particularly helpful.

When researchers looked at biopsies taken before and after immunotherapy, they found that patients who developed these structures had structures that resembled precursors of tertiary lymphoid structures before they began treatment. When the study’s lead author, Daniel Shu, MD, then a medical oncologist at Johns Hopkins, examined the areas where patients’ tumors had been eliminated, he discovered a transformation in the remaining tertiary lymphoid structures in the area.

“In the tumors where immunotherapy had the greatest effect, we found another, previously unseen form of tertiary lymphoid structure. In this form, there was a distribution of B cells and a marked retention of areas called T-cell domains, where T cells are primed to recognize antigens,” says Shu. currently at the University of Maryland School of Medicine. “The same patients tend to derive the greatest benefit from immunotherapy given in this manner. Although more studies are needed, our hypothesis is that this form is a late stage of the tertiary lymphoid structure and may contribute to the long-term benefit we see in these patients.”

The team’s next step is to determine whether they can trigger the formation of tertiary lymphoid structures in patients who do not improve on their own after starting immunotherapy. They also plan to look at how different combinations of immunotherapies or other presurgical treatments affect tertiary lymphoid structure formation and patient outcomes. This discovery may also have implications for other types of cancer, as the new form of tertiary lymphoid structure reported here was also seen by the authors in two other tumor types known to respond to immunotherapy.

The study was a collaborative effort of the imCORE Network and one of the study’s co-leaders Elana Fertig, Ph.D.professor of oncology and biomedical engineering; oncology quantitative sciences division director; and co-director of the Convergence Institute at Johns Hopkins. Co-authors of the study include: Won Jin Ho, Luciane Kagohara, Alexander Girgis, Sarah Shin, Ludmila Danilova, Jae Lee, Dimitrios Sidiropoulos, Sarah Mitchell, Kabeer Munjal, Kathryn Howe, Kayla Bendinelli, Emma Kartalia, Hanfei Qi, Guanglan Mo, Janelle Montagne, James Leatherman, Tamara Lopez-Vidal, Qingfeng Zhu, Amanda Huff, Xuan Yuan, Alexei Hernandez, Erin Coyne, Neeha Zaidi, Daniel Zabransky, Logan Engle, Aleksandra Ogurtsova, Marina Baretti, Daniel Laheru, Jennifer Durham, Hao Wang, Joel Sunshine, Julie Stein Deutsch, Janis Taube, Robert Anders and Elizabeth Jaffee Johns Hopkins. Robert Johnston Genentech also contributed.

The study was funded by F. Hoffmann-La Roche, Johns Hopkins SPORE in Gastrointestinal Cancer, National Institutes of Health, Breeden-Adams Foundation, Conquer Cancer, Johns Hopkins University School of Medicine J. Mario Molina Physician Scientist Fund, and Maryland Cancer Moonshot.

Yarchoan has received funding or consulting fees from AstraZeneca, Exelixis, Genentech, Replimune, Hepion, Lantheus, Bristol-Myers Squibb, Exelixis, and Incyte. He also co-founded and owns shares of Adventris Pharmaceuticals. Fertig sits on the scientific advisory board of Viosera/Resistance Bio, is a paid consultant to Merck and Mestag Therapeutics, and receives research funding from Abbvie. Ho has received patent royalties from Rodeo/Amgen and grants or honoraria from Sanofi, NeoTX, CirclePharma, Exelixis, and Standard BioTools. Jaffee has received grants/research support or honoraria from the Lustgarten Foundation, Break Through Cancer, Roche/Genentech, Bristol-Meyers Squibb, Achilles, DragonFly, Parker Institute, Texas Institute for Cancer Prevention and Research, Surge, HDT Bio, Mestag Therapeutics and Medical. reported the Home Group. He also owns shares in AbMeta Therapeutics and Adventris Pharmaceuticals. Zabransky reports grant/research support from Roche/Genentech. Taube reports receiving research funding from BMS and Akoya Biosciences. He also serves as a consultant to BMS, Merck, Astra Zeneca, Genentech, Regeneron, Elephas, Lunaphore, Compugen, and Akoya Biosciences, and holds shares in Akoya Biosciences. These relationships are managed by Johns Hopkins University in accordance with its conflict of interest policies.

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