Liver and Bile
Nat Immunol. 2024(11):2110-2123
Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma
Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade, but understanding of the prognostic and predictive value of TLS and the circumstances of their resolution is incomplete. Here the authors show that in hepatocellular carcinoma treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse-free survival. In areas of tumor regression, they identify a non-canonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions and increased expression of T cell memory markers. Collectively, these data suggest that TLS can serve as both a prognostic and predictive marker of response to immunotherapy in hepatocellular carcinoma and that late-stage TLS may support T cell memory formation after elimination of a viable tumor.
DOI: 10.1038/s41590-024-01992-w
DOI: 10.1038/s41590-024-01992-w
Section Head for Translational Systems Immunology in Hepatogastroenterology, Department of Internal Medicine II, University Medical Center Freiburg (Germany)
Tertiary Lymphoid Structure Changes in HCC Immunotherapy – Novel Type with Predictive Potential?
The development of ectopic “tertiary” lymphoid structures (TLS) in non-lymphoid organs is observed in cancers such as hepatocellular carcinoma (HCC). The formation of TLS is considered to be transient and driven by an inflammatory microenvironment. Their presence is associated with reduced early recurrence after HCC resection (Calderaro et al., DOI: 10.1016/j.jhep.2018.09.003) and has been identified as a positive predictor for checkpoint therapy across multiple cancers. However, TLS may potentially also serve as a niche for malignant cells (Finkin et al., DOI: 10.1038/ni.3290). The biology of TLS is not fully understood. Different stages of TLS maturation are recognized among which a “mature” TLS stage is defined based on the presence of germinal center (GC) organization similar to secondary lymphoid tissue, involving GC B cells, T cells, follicular dendritic cells, fibroblastic reticular cells, and specialized high endothelial venules, all in a spatially clearly organized follicular structure. However, many distinct variants of TLS have been found and early stages of TLS maturation may involve only few immune cell aggregates.
In their current study, Shu et al. analyzed TLS in patients with HCC who underwent tumor resection following neoadjuvant checkpoint therapy. They found that the presence of CD20+CXCL13+ lymphatic aggregates in pretreatment fine-needle aspirates was associated with a pathologic response at resection. Moreover, they observed a correlation between TLS density and both pathologic response and relapse-free survival at resection. However, the authors identified novel types of TLS morphology extending beyond the traditional 3-phase TLS trajectory of lymphoid aggregates, immature TLS, and mature TLS. In areas of tumor regression, the authors identified a distinct TLS morphology that they termed “involuted.” These involuted TLS are characterized by a decrease in B cells and disrupted follicular organization but enhanced T cell-dendritic cell interactions within the T-cell zone. Transcriptional and clonal analyses after microdissection indicated that involuted TLS serve as sites of B-cell hypermutation and exhibit more diverse T-cell repertoires. The authors also observed a higher number of memory T cells in involuted lymph nodes.
The study thus highlights the post-therapeutic involuted TLS as a correlate of successful immunotherapy. The data suggest that these structures are enriched for tumor-reactive lymphocytes and may play a role in tumor-specific memory. Nevertheless, our mechanistic understanding of TLS formation and maturation requires further study. Strategies to induce TLS during checkpoint therapy warrant further exploration.