A newly described stage of lymph node–like structures, known as tertiary lymphoid structures, identified in hepatic tumors following presurgical immunotherapy may be vital to successfully treating patients with hepatocellular carcinoma, according to a recent study published by Shu et al in Nature Immunology.
Background
Tertiary lymphoid structures—highly organized collections of immune B and T cells—are found in some patients treated with immune checkpoint inhibitors and are associated with a greater treatment response. However, prior studies have not yet uncovered how these structures may contribute to immune responses to cancer, how they change over time, and what their presence in tumors means for patients.
A previous study of immunotherapy prior to surgery in patients with hepatocellular carcinoma demonstrated that only some of these patients were cured with this approach. After investigation, the study researchers noted that like lymph nodes, tertiary lymphoid structures have infection-fighting immune B cells in the middle and tumor-killing immune T cells on the outside.
“One of the things that struck us when we looked at these tumors was that patients who were responding to immunotherapy had tertiary lymphoid structures,” explained senior study author Mark Yarchoan, MD, Associate Professor of Oncology at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center. “We wanted to learn what these structures are doing,” he added.
Study Methods and Results
In the recent study, the researchers identified a previously unknown type of tertiary lymphoid structures. They found that the patients who had more of these structures were less likely to experience cancer recurrence postsurgery.
Additionally, the researchers discovered that the tumors with more tertiary lymphoid structures following immunotherapy shrank more and were less likely to recur following surgical removal. By contrast, tumors without these structures didn’t shrink and were more likely to recur following surgery. Tertiary lymphoid structures that grew in the center of tumors rather than around the edges were particularly beneficial.
After examining biopsies taken prior to and following immunotherapy, the researchers revealed that the patients who developed the structures presented with what looked like precursors of tertiary lymphoid structures prior to the initiation of therapy. The researchers then analyzed the sites where the patients’ tumors had been eliminated and observed a transformation in the tertiary lymphoid structures remaining at the site.
“In tumors where immunotherapy had the greatest effect, we found another form of tertiary lymphoid structure that has not been seen before. In this [type], there was dispersion of B cells and apparent retention of so-called T-cell zones, where T cells are primed to identify antigens,” emphasized lead study author Daniel Shu, MD, of the University of Maryland School of Medicine. “These same patients tend to have the greatest benefit from immunotherapy given in this way,” he underlined.
Conclusions
“We identified the life cycle of tertiary lymphoid structures in patients with [hepatocellular carcinoma], and the takeaway is that these structures may be very important in the generation of antitumor immunity and may increase the likelihood of curing the cancer,” highlighted Dr. Yarchoan.
The researchers plan to determine if they can induce the formation of tertiary lymphoid structures in patients who don’t develop them on their own after starting immunotherapy. They also hope to explore how different combinations of immunotherapies or other presurgical therapies could affect tertiary lymphoid structure formation and patient outcomes. The discovery may have implications for other types of cancers, since the new type of tertiary lymphoid structure reported in the study was also seen by the researchers in two other types of tumors known to respond to immunotherapy.
“While a lot more work needs to be done, our hypothesis is that this [type] is a late stage of tertiary lymphoid structure that may contribute to long-term benefit we are seeing in these patients,” concluded Dr. Shu.
Disclosure: The research in this study was supported by F. Hoffmann-La Roche, the Johns Hopkins SPORE in Gastrointestinal Cancer, the National Institutes of Health, the Breeden-Adams Foundation, Conquer Cancer, the Johns Hopkins University School of Medicine J. Mario Molina Physician Scientist Fund, and the Maryland Cancer Moonshot. For full disclosures of the study authors, visit nature.com.
