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•Intra-tumoral tertiary lymphoid structures are associated with decreased risk of early HCC relapse after surgery.•Presence of intra-tumoral tertiary lymphoid structures is not linked ...to the etiology of the underlying liver disease.•Our study suggests that tertiary lymphoid structures reflect ongoing, effective anti-tumor immunity.
Tertiary lymphoid structures (TLSs) provide a local and critical microenvironment for generating anti-tumor cellular and humoral immune responses. TLSs are associated with improved clinical outcomes in most solid tumors investigated to date. However, their role in hepatocellular carcinoma (HCC) is debated, as they have recently been shown to promote the growth of malignant hepatocyte progenitors in the non-tumoral liver.
We aimed to determine, by pathological review, the prognostic significance of both intra-tumoral and non-tumoral TLSs in a series of 273 patients with HCC treated by surgical resection in Henri Mondor University Hospital. Findings were further validated by gene expression profiling using a public data set (LCI cohort).
TLSs were identified in 47% of the tumors, by pathological review, with lymphoid aggregates, primary and secondary follicles in 26%, 16% and 5% of the cases, respectively. Univariate and multivariate analyses showed that intra-tumoral TLSs significantly correlated with a lower risk of early relapse (<2 years after surgery, hazard ratio 0.46, p = 0.005). Interestingly, the risk of recurrence was also related to the degree of TLS maturation (primary or secondary follicles vs. lymphoid aggregates, p = 0.01). A gene expression signature associated with the presence of intra-tumoral TLS was also independently associated with a lower risk of early relapse in the LCI cohort. No association between the density of TLSs located in the adjacent non-tumoral liver and early or late recurrence was observed.
We have shown that intra-tumoral TLSs are associated with a lower risk of early relapse in 2 independent cohorts of patients with HCC treated by surgical resection. Thus, intra-tumoral TLSs may reflect the existence of ongoing, effective anti-tumor immunity.
Tertiary lymphoid structures provide a critical microenvironment for generating anti-tumor immune responses, and are associated with improved clinical outcome in most cancers investigated. Their role in hepatocellular carcinoma is however debated. We show in the present study that intra-tumoral tertiary lymphoid structures are associated with a low risk of early relapse after surgical resection, suggesting that they reflect the existence of in situ, effective anti-tumor immunity.
The Lhasa Terrane in southern Tibet has long been accepted as the last geological block accreted to Eurasia before its collision with the northward drifting Indian continent in the Cenozoic, but its ...lithospheric architecture, drift and growth histories and the nature of its northern suture with Eurasia via the Qiangtang Terrane remain enigmatic. Using zircon in situ U–Pb and Lu–Hf isotopic and bulk-rock geochemical data of Mesozoic–Early Tertiary magmatic rocks sampled along four north–south traverses across the Lhasa Terrane, we show that the Lhasa Terrane has ancient basement rocks of Proterozoic and Archean ages (up to 2870Ma) in its centre with younger and juvenile crust (Phanerozoic) accreted towards its both northern and southern edges. This finding proves that the central Lhasa subterrane was once a microcontinent. This continent has survived from its long journey across the Paleo-Tethyan Ocean basins and has grown at the edges through magmatism resulting from oceanic lithosphere subduction towards beneath it during its journey and subsequent collisions with the Qiangtang Terrane to the north and with the Indian continent to the south. Zircon Hf isotope data indicate significant mantle source contributions to the generation of these granitoid rocks (e.g., ~50–90%, 0–70%, and 30–100% to the Mesozoic magmatism in the southern, central, and northern Lhasa subterranes, respectively). We suggest that much of the Mesozoic magmatism in the Lhasa Terrane may be associated with the southward Bangong–Nujiang Tethyan seafloor subduction beneath the Lhasa Terrane, which likely began in the Middle Permian (or earlier) and ceased in the late Early Cretaceous, and that the significant changes of zircon εHf(t) at ~113 and ~52Ma record tectonomagmatic activities as a result of slab break-off and related mantle melting events following the Qiangtang–Lhasa amalgamation and India–Lhasa amalgamation, respectively. These results manifest the efficacy of zircons as a chronometer (U–Pb dating) and a geochemical tracer (Hf isotopes) in understanding the origin and histories of lithospheric plates and in revealing the tectonic evolution of old orogenies in the context of plate tectonics.
►The central Lhasa subterrane was once a microcontinent with ancient basement rocks of Proterozoic and Archean ages, whereas the southern and northern portions are more recently accreted subterranes during its journey of drift across the Tethyan Ocean basins.►Much of the Mesozoic magmatism in the Lhasa Terrane may be associated with the southward Bangong–Nujiang Tethyan seafloor subduction beneath the Lhasa Terrane, which likely began in the late Middle Permian (~263Ma or earlier) and ceased in the late Early Cretaceous (~113Ma).►The Neo-Tethyan Ocean seafloor must have subducted northward beneath the southern Lhasa subterrane, which likely initialized in the very Early Cretaceous.►The significant changes of zircon εHf(t) at ~113 and ~52Ma record tectonomagmatic activities as a result of slab break-off and related mantle melting events following the Qiangtang–Lhasa amalgamation and India–Lhasa amalgamation, respectively.
We previously proposed an immune cell score (tumour node metastasis (TNM)-Immune cell score) classifier as an add-on to the existing TNM staging system for non-small cell lung cancer (NSCLC). Herein, ...we examined how to reliably assess a tertiary lymphoid structure (TLS) score to refine the TNM staging system.
Using immunohistochemistry (CD8/cytokeratin), we quantified TLS in resected NSCLC whole-tumour tissue sections with three different scoring models on two independent collections (total of 553 patients). In a pilot setting, NanoString gene expression signatures were analysed for associations with TLS.
The number of TLSs significantly decreased in stage III patients as compared to stage II. The TLS score was an independent positive prognostic factor, regardless of the type of (semi)-quantification strategy used (four-scale semi-quantitative; absolute count of total TLS; subpopulation of mature TLS) or the endpoint (disease-specific survival; overall survival; time to recurrence). Subgroup analyses revealed a significant prognostic impact of TLS score within each pathological stage, patient cohort and main histological subtype. Targeted gene expression analysis showed that high TLS levels were associated with the expression of B cell and adaptive immunity genes/metagenes including tumour inflammation signature.
The TLS score increases the prognostic power in each pathological stage and hence has the potential to refine TNM staging in resected NSCLC.
In solid tumors, the presence of lymph node-like structures called tertiary lymphoid structures (TLS) is associated with improved patient survival. However, little is known about how TLS develop in ...cancer, how their function affects survival, and whether they are affected by cancer therapy. In this study, we used multispectral microscopy, quantitative pathology, and gene expression profiling to analyze TLS formation in human lung squamous cell carcinoma (LSCC) and in an experimental model of lung TLS induction. We identified a niche of CXCL13
perivascular and CXCL12
LTB
and PD-L1
epithelial cells supporting TLS formation. We also characterized sequential stages of TLS maturation in LSCC culminating in the formation of germinal centers (GC). In untreated patients, TLS density was the strongest independent prognostic marker. Furthermore, TLS density correlated with GC formation and expression of adaptive immune response-related genes. In patients treated with neoadjuvant chemotherapy, TLS density was similar, but GC formation was impaired and the prognostic value of TLS density was lost. Corticosteroids are coadministered with chemotherapy to manage side effects in LSCC patients, so we evaluated whether they impaired TLS development independently of chemotherapy. TLS density and GC formation were each reduced in chemotherapy-naïve LSCC patients treated with corticosteroids before surgery, compared with untreated patients, a finding that we confirmed in the experimental model of lung TLS induction. Overall, our results highlight the importance of GC formation in TLS during tumor development and treatment.
Corticosteroid treatment during chemotherapy negatively affects the development of tertiary lymphoid structures and abrogates their prognostic value in patients with lung cancer.
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Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in ...certain inflammation‐associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour‐associated TLSs remain ill‐defined. Here, we observed tumour‐associated TLSs in a preclinical mouse model (gp130F/F) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL‐6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell‐rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130‐driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3‐dependent, but independent of the cytokine IL‐17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour‐associated TLSs were also observed in patients with intestinal‐type gastric cancer, and a gene signature linked with TLS development in gp130F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130‐STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis.
What's new?
Tertiary lymphoid structures (TLSs) develop in chronically inflamed tissues, and have been associated with improved survival in certain cancer patients. Here, the authors examined mechanisms governing the development of submucosal TLSs in the gp130F/F mouse model of gastric cancer and in patients afflicted with intestinal‐type disease. TLS formation was observed both mice and patients but a TLS gene signature identified in mice did not predict improved patient survival, pointing to need for more research into TLSs and gastric cancer prognosis.
The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to ...examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.
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•Tertiary lymphoid structures are sites of in situ B cell maturation toward plasma cells•IgG+ and IgA+ plasma cells disseminate into the tumor tissue along fibroblastic tracks•Tumor cells are labeled by locally produced IgG•Patients with IgG-labeled tumor cells have high response rate to ICI and prolonged PFS
Meylan et al. show that tertiary lymphoid structures found in tumors are sites of generation of fully mature B cell immunity. Plasma cells disseminate into tumor beds, producing antibodies that bind to tumor cells and initiate their apoptosis, providing a mechanism to support cancer immunotherapies that modulate the tumor microenvironment.
High endothelial venules (HEVs) are specialized postcapillary venules composed of cuboidal blood endothelial cells that express high levels of sulfated sialomucins to bind L-Selectin/CD62L on ...lymphocytes, thereby facilitating their transmigration from the blood into the lymph nodes (LN) and other secondary lymphoid organs (SLO). HEVs have also been identified in human and murine tumors in predominantly CD3
T cell-enriched areas with fewer CD20
B-cell aggregates that are reminiscent of tertiary lymphoid-like structures (TLS). While HEV/TLS areas in human tumors are predominantly associated with increased survival, tumoral HEVs (TU-HEV) in mice have shown to foster lymphocyte-enriched immune centers and boost an immune response combined with different immunotherapies. Here, we discuss the current insight into TU-HEV formation, function, and regulation in tumors and elaborate on the functional implication, opportunities, and challenges of TU-HEV formation for cancer immunotherapy.
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