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Late-stage tertiary lymphoid structures in hepatocellular carcinoma treated with neoadjuvant immune checkpoint blockade [scRNA-seq]

ABSTRACT: Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade (ICB), but understanding of their clinical significance and the circumstances of their resolution remains incomplete. Here, we found that in hepatocellular carcinoma (HCC) 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, we further identified 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 may serve be both a prognostic and predictive marker of response to immunotherapy in HCC and suggest a functional role for late-stage TLS T cell memory formation after elimination of viable tumor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272347 | GEO | 2024/09/13

REPOSITORIES: GEO

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Late-stage tertiary lymphoid structures in hepatocellular carcinoma treated with neoadjuvant immune checkpoint blockade [bulk RNA-seq]

Project description:Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade (ICB), but understanding of their clinical significance and the circumstances of their resolution remains incomplete. Here, we found that in hepatocellular carcinoma (HCC) 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, we further identified 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 may serve be both a prognostic and predictive marker of response to immunotherapy in HCC and suggest a functional role for late-stage TLS T cell memory formation after elimination of viable tumor.

2024-09-13 | GSE272346 | GEO

Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer

Project description: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.

2022-03-03 | GSE175540 | GEO

Tertiary Lymphoid Structure Raises Survival and Immunotherapy in HPV- HNSCC

Project description:The presence of B cells in tumors have been recently reported to predict the better prognosis of patients with cancer. B cells were found primarily in so-called tertiary lymphoid structures (TLSs) in tumor. TLSs are ectopic lymphoid aggregates that form at sites of micro-secondary lymphoid organs, including a B cell follicle with a network of follicular dendritic cells (FDCs) surrounded by T cell zone composed of CD4+ T follicular helper (Tfh) cells and CD8+ T cells and high endothelial venules (HEVs). The presence of TLS is associated with positive outcomes in several human malignancie and More importantly, TLSs enriched in B cells have been proven beneficial for response to ICB in multiple types of cancer. Here, we establish tobacco-associated HNSCC mouse model with TLS enrichment by overexpression of LIGHT in tumor to evaluate the TLS influence in HPV- HNSCC and immunotherapy in HPV- HNSCC.

2022-03-03 | GSE197559 | GEO

Tumoral and stromal hMENA isoforms influence tertiary lymphoid structure localization and predict response to immunocheckpoint blockade in lung cancer patients

Project description:The advent of immunotherapy in the clinical practice of non-small cell lung cancer (NSCLC) have highlighted the impact of the tumor immune microenvironment in the control of the tumor progression, as well as in the response to immune checkpoint blockade (ICB) therapy. Tertiary Lymphoid Structures (TLS), determinants of antitumor immunity, are associated with a favorable clinical outcome in NSCLC patients and with the effectiveness of ICB in several tumors. The actin regulatory protein hMENA undergoes tissue-specific splicing, with tumors expressing hMENA11ahigh/ stromal fibronectin (FN1)low related to early N0 NSCLC patients with a favorable prognosis. hMENA/hMENA∆v6 is overexpressed in pro-tumoral CAFs related to the subtype of immunosuppressive ECM-my-CAF Herein, by analyzing the pattern of hMENA isoform expression in tumor cells and CAFs, we highlighted the role of hMENA as a crucial factor in the communication among tumor cells CAFs, T and B cells. Mechanistically, we demonstrated that in NSCLC cell lines hMENA11a increases the expression of the TLS regulator LTβR, reduces the FN1 expression and favors CXCL13 production by tissue resident T cells. Conversely in CAFs, hMENA/hMENAΔv6 inhibits the NF-kB pathway downstream to LTβR and the secretion of CXCL13, crucial in TLS formation. Of clinical relevance, our experimental data support our finding in primary tumors that TLS localized within the tumor area (TLS-IT) are predictive of a longer disease-free survival in N0 NSCLC patients and are accompanied by the maturation of B cells in the tumor tissue. TLS-IT associate with paucity of hMENA positive CAFs, low stromal FN1 and high hMENA11a tumor cell expression. To translate these results in a clinical setting of ICB treated patients, we identified a signature based on the pattern of hMENA isoforms, FN1 and LTβR expression that may discriminate NSCLC patients responding or not-responding to ICB.

2023-08-30 | GSE217451 | GEO

Loss of Vascular Endothelial Notch Signaling Induces Tertiary Lymphoid Structures in the Kidney

Project description:Tertiary lymphoid structures (TLS are lymph node-like immune cell clusters that emerge during chronic inflammation in non-lymphoid organs like the kidney, but their origin remains not well understood. Here we show, using conditional deletion strategies of the canonical Notch signaling mediator Rbpj, that loss of endothelial Notch signaling in adult mice induces the spontaneous formation of bona fide TLS in the kidney, liver and lung, based on molecular, cellular and structural criteria. These TLS form in a stereotypical manner around parenchymal arteries, while secondary lymphoid structures remained largely unchanged. This effect is mediated by endothelium of blood vessels, but not lymphatics, since a lymphatic endothelial-specific targeting strategy did not result in TLS formation, and involves loss of arterial specification and concomitant acquisition of a high endothelial cell phenotype, as shown by transcriptional analysis of kidney endothelial cells. This indicates a so far unrecognized role for vascular endothelial cells and Notch signaling in TLS initiation.

2022-02-24 | GSE193544 | GEO

Kidney tertiary lymphoid structures in Lupus Nephritis develop into large interconnected networks and resembles lymph nodes in gene signature.

Project description:Immune aggregates organized as tertiary lymphoid structures (TLS) are observed within kidneys of systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). We characterized renal TLS in lupus-prone (NZBxNZW) F1 mice with respect to cell composition and vessel formation. Ribonucleic acid (RNA) sequencing was performed on transcriptomes isolated from Lymph nodes (LyN), macro-dissected TLS from kidneys, and total kidneys of mice at different disease stages by using Ion Torrent Personal Genome Machine (Ion PGM) and RNAseq from Illumina. Formation of TLS was found in anti-dsDNA antibody positive mice and the structures were organized as interconnected large networks with distinct T and B cell zones with adjacent dendritic cells, macrophages, plasma cells, high endothelial venules, supporting follicular dendritic cells network, and functional germinal centers. Comparison of gene profiles of whole kidney, renal TLS and LyN revealed a similar gene signature of TLS and LyN. The upregulated genes within the kidneys of lupus-prone mice during the development of LN reflected the TLS formation, while the downregulated genes were involved in metabolic processes of the kidney cells. A comparison with human LN gene expression revealed similar upregulated genes as observed during the development of murine LN and TLS. We conclude that kidney TLS have a similar cell composition, structure and gene signature as LyN, and therefore may function as a kidney specific type of LyN.

2020-07-30 | GSE155405 | GEO

Stimulation of tumor infiltrating B-cells improves ex-vivo TIL expansion for melanoma sample immunotherapy I

Project description:Many studies have shown association of tumor infiltrating B-cells and presence of tertiary lymphoid structure with improved clinical responses to immune checkpoint inhibitors therapy. We hypothesized that their presence could also have an impact on TIL therapy response. To address this, we performed RNA-seq of FFPE samples from a cohort of patients that received TIL therapy. Melanoma tumors collected prior to TIL infusion were evaluated for immune content in 9 responders and 11 non-responders to TIL therapy. Our data demonstrate an increase in class-switched memory B-cells in responders compared with non-responders to TIL therapy. In the myeloid compartment, increased presence of dendritic cell populations (pDC, aDC, and iDC) and basophils was observed in responders to TIL therapy, as well as higher content of γδ T cells and effector memory CD8+ T cells (CD8+ Tem) in the T-cell compartment. Next, we assessed the TLS presence in the same cohort by a gene expression signature of 12 chemokines using principal component analysis. The responders showed a higher TLS score compared with the non-responder patients, suggesting that patients responding to TIL therapy had more TLS in their tumors than the non-responder patients. These observations indicate that, same as in the immune checkpoint inhibitors therapy response, presence of B-cells and TLS might have a positive impact in the clinical outcome to TIL therapy.

2024-06-30 | GSE217387 | GEO

Single-cell profiling of tumor-infiltrating TCF7+ T cells reveals a T lymphocyte subset associated with tertiary lymphoid structures and superior prognosis in oral cancer

Project description:We isolated OSCC cells and performed single-cell RNA sequencing(scRNA-seq). Using immunohistochemistry(IHC) to analyze the relationship between TLS and prognosis. Multiple immunohistochemistry (MIHC), Flow cytometry (FCM) and Spatial analysis were used to verify the characteristics of TCF7+ T cells and their correlation with TLS. The prognostic significance, upstream regulatory network and intercellular communication of the TCF7+ T cell subpopulation were performed by multivariate analysis, Scenic and CellPhone software package analysis.We found a strong association between TCF7+ T cell subsets, TLSs and prognosis. The results suggested that TCF7+ T cells are expressing high levels of TLS-related genes and low levels of immune checkpoint molecules. Finally, we found that TCF7+ T cells were significantly associated with favorable outcomes. We also describe the upstream drivers and intercellular molecules that these cells rely on.The results showed that TCF7+ T cells could be used as a new therapeutic target to regulate the immune response of OSCC and are expected to be a new prognostic marker.

2021-08-13 | GSE172577 | GEO

Enhancement of anti-tumor immunity by tertiary lymphoid structures in esophageal squamous cell carcinoma

Project description:Our study showed that TLS enhanced anti-tumor immunity in ESCC.

2023-08-31 | GSE209524 | GEO

Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis

Project description:Tertiary lymphoid structures (TLSs) are associated with anti-tumor response following immune checkpoint inhibitor (ICI) therapy, but a commensurate observation of TLS is absent for immune related adverse events (irAEs) i.e. acute interstitial nephritis (AIN). We hypothesized that TLS-associated inflammatory gene signatures are present in AIN and performed NanoString-based gene expression and multiplex 12-chemokine profiling on paired kidney tissue, urine and plasma specimens of 36 participants who developed acute kidney injury (AKI) on ICI therapy: AIN (18), acute tubular necrosis (9), or HTN nephrosclerosis (9). Increased T and B cell scores, a Th1-CD8+ T cell axis accompanied by interferon-Ã¯ÂÂ§ and TNF superfamily signatures were detected in the ICI-AIN group. TLS signatures were significantly increased in AIN cases and supported by histopathological identification

| EGAS00001006781 | EGA

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