tertiary lymphoid structures
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PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262455
Author(s):  
Takuya Mori ◽  
Hiroaki Tanaka ◽  
Sota Deguchi ◽  
Yoshihito Yamakoshi ◽  
Yuichiro Miki ◽  
...  

Nivolumab, an immune checkpoint blocker, has been approved for advanced gastric cancer (GC), but predictive factors of nivolumab’s efficacy in patients with GC, especially immune cells such as tissue-resident memory T cells or those forming tertiary lymphoid structures (TLS), remain unclear. Tissue samples were obtained from surgically resected specimens of patients with GC who were treated with nivolumab as third-line or later treatment. Immunohistochemical staining was performed to detect the presence of TLS and CD103+ T cells and assess the association between TLSs and response to nivolumab treatment. A total of 19 patients were analyzed. In patients with partial response (PR) to nivolumab, numerous TLS were observed, and CD103+ T cells were found in and around TLS. Patients with many TLS experienced immune-related adverse events more often than those with few TLS (p = 0.018). The prognosis of patients with TLS high was better than those with TLS low. Patients with a combination of TLS high and CD103 high tended to have a better prognosis than other groups. Our results suggested that TLS status might be a predictor of nivolumab effectiveness.


Science ◽  
2022 ◽  
Vol 375 (6576) ◽  
Author(s):  
Ton N. Schumacher ◽  
Daniela S. Thommen

Immunity ◽  
2022 ◽  
Vol 55 (1) ◽  
pp. 115-128.e9
Author(s):  
Ricardo A. Chaurio ◽  
Carmen M. Anadon ◽  
Tara Lee Costich ◽  
Kyle K. Payne ◽  
Subir Biswas ◽  
...  

2021 ◽  
pp. clincanres.1130.2021
Author(s):  
Martin Lauss ◽  
Marco Donia ◽  
Inge Marie Svane ◽  
Göran Jönsson

2021 ◽  
Vol 12 ◽  
Author(s):  
Nick van Dijk ◽  
Alberto Gil-Jimenez ◽  
Karina Silina ◽  
Maurits L. van Montfoort ◽  
Sarah Einerhand ◽  
...  

Candidate immune biomarkers have been proposed for predicting response to immunotherapy in urothelial cancer (UC). Yet, these biomarkers are imperfect and lack predictive power. A comprehensive overview of the tumor immune contexture, including Tertiary Lymphoid structures (TLS), is needed to better understand the immunotherapy response in UC. We analyzed tumor sections by quantitative multiplex immunofluorescence to characterize immune cell subsets in various tumor compartments in tumors without pretreatment and tumors exposed to preoperative anti-PD1/CTLA-4 checkpoint inhibitors (NABUCCO trial). Pronounced immune cell presence was found in UC invasive margins compared to tumor and stroma regions. CD8+PD1+ T-cells were present in UC, particularly following immunotherapy. The cellular composition of TLS was assessed by multiplex immunofluorescence (CD3, CD8, FoxP3, CD68, CD20, PanCK, DAPI) to explore specific TLS clusters based on varying immune subset densities. Using a k-means clustering algorithm, we found five distinct cellular composition clusters. Tumors unresponsive to anti-PD-1/CTLA-4 immunotherapy showed enrichment of a FoxP3+ T-cell-low TLS cluster after treatment. Additionally, cluster 5 (macrophage low) TLS were significantly higher after pre-operative immunotherapy, compared to untreated tumors. We also compared the immune cell composition and maturation stages between superficial (submucosal) and deeper TLS, revealing that superficial TLS had more pronounced T-helper cells and enrichment of early TLS than TLS located in deeper tissue. Furthermore, superficial TLS displayed a lower fraction of secondary follicle like TLS than deeper TLS. Taken together, our results provide a detailed quantitative overview of the tumor immune landscape in UC, which can provide a basis for further studies.


2021 ◽  
Author(s):  
Miriam I Rosenberg ◽  
Erez Greenstein ◽  
Martin Buchkovich ◽  
Martin Mikl ◽  
Ayelet Peres ◽  
...  

Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop Opsoclonus Myoclonus Ataxia Syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity, but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor infiltrating T- and B-cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS associated neuroblastomas. We found greater B- and T-cell infiltration in OMAS-associated tumors compared to controls, but unexpectedly showed that both were polyclonal expansions. Tertiary lymphoid structures (TLS) were enriched in OMAS-associated tumors. We identified significant enrichment of the MHC Class II allele HLA-DOB*01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal autoreactive B lymphocytes act as antigen presenting cells and drive TLS formation, thereby crucially supporting both sustained polyclonal T-cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.


2021 ◽  
Author(s):  
Chiara Sorini ◽  
Kumar P. Tripathi ◽  
Shengru Wu ◽  
Shawn M. Higdon ◽  
Jing Wang ◽  
...  

ABSTRACTObjectiveHelicobacter pylori colonization of the gastric niche can persist for years in asymptomatic individuals. Although latent H. pylori infection can progress to cancer, a detailed survey of the microbiome and immune composition in the chronically infected stomach is still lacking.DesignWe collected human gastric tissues and performed metagenomic sequencing, single-cell RNA sequencing (scRNA-seq), flow cytometry and fluorescent microscopy to deeply characterize the host-microbiota environment in H. pylori-infected (HPI) stomachs.ResultsHPI asymptomatic individuals showed dramatic changes in the composition of gastric microbiome and immune cells compared to non-infected individuals. With metagenomic data, we also demonstrated antibiotic resistant genes, enzymes and pathway alterations related to metabolism and immune response. scRNA-seq and flow cytometry data revealed that in contrast to murine stomachs, ILC2 are virtually absent in the human gastric mucosa, whereas ILC3 are the dominant population in asymptomatic HPI individuals. Specifically, NKp44+ ILC3s were highly increased in the gastric mucosa of asymptomatic HPI individuals, and their proportions correlated with the abundance of selected microbial taxa found to be enriched in the infected mucosa. In addition, CD11c+ myeloid cells, activated CD4 T cells and B cells were expanded in HPI individuals. In HPI individuals, B cells acquired an activated phenotype and progressed into a highly proliferating germinal center stage and plasmablast maturation, which correlated with the presence of tertiary lymphoid structures within the gastric lamina propria.ConclusionOur study provides a comprehensive atlas of the gastric mucosa-associated microbiome and immune cell landscape when comparing asymptomatic HPI and uninfected individuals.SIGNIFICANCE OF THE STUDYWhat is already known on this subject? Previous studies on the gastric microbiome were performed via 16S rRNA gene sequencing.Acute Helicobacter spp. infection in murine models and symptomatic H. pylori-driven pathology in humans result in remodeling of the stomach immune cell compartment.ILC2 is the dominant ILC population in the murine stomach.What are the new findings? We described the effect of chronic asymptomatic H. pylori infection on the gastric microbiome via whole-genome sequencing.Single cell census of the gastric mucosa reveals ILC3 to be the dominant ILC population in the human stomach, whereas ILC2 were virtually absent.scRNA-seq reveals the gastric immune cell programs in asymptomatic H. pylori-infected individuals, which is characterized by the formation of tertiary lymphoid structures.How might it impact on clinical practice in the foreseeable future? Whole genome sequencing of uninfected and H. pylori-infected gastric mucosa bolsters collective knowledge of stomach physiology with respect to the gastric microbiome and microbiota function.We present a comprehensive immune cellular landscape of the human stomach, which will be a valuable resource to interrogate pathology of gastric diseases.


2021 ◽  
Author(s):  
Masayo Ukita ◽  
Junzo Hamanishi ◽  
Hiroyuki Yoshitomi ◽  
Koji Yamanoi ◽  
Shiro Takamatsu ◽  
...  

Background: Tertiary lymphoid structures (TLSs) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. The presence of TLS is associated with a favorable prognosis in most solid malignancies. The recognition of the relevance of TLS to cancer has led to a growing interest in TLS as an immunomodulatory target to enhance tumor immunity, although how TLSs are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. Methods: TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression were investigated in high grade serous ovarian cancer (HGSC) specimens. CXCL13 expression, which is strongly associated with TLS, and its localization in immune cells, were examined. We explored the tumor microenvironment for CXCL13 secretion by adding various inflammatory cytokines in vitro. The induction of TLS by CXCL13 was examined in a mouse model of ovarian cancer. Results: CXCL13 gene expression correlated with TLS formation and the infiltration of T cells and B cells, and was a favorable prognostic factor for HGSC patients. The coexistence of CD8+ T cells and B-cell lineages in the TME was associated with a better prognosis of HGSC and was closely related to the presence of TLSs. CXCL13 expression was predominantly coincident with CD4+ T cells in TLSs and CD8+ T cells in TILs, and shifted from CD4+ T cells to CD21+ follicular dendritic cells as the TLS matured. Although TGF-β was reported to stimulate CXCL13 production, our in vitro results revealed that CXCL13 secretion was promoted in CD4+ T cells under TGF-β + IL-2-restricted conditions and in CD8+ T cells under TGF-β + IL-12-rich conditions. In a mouse model of ovarian cancer, recombinant CXCL13 induced TLSs and enhanced survival by the infiltration of CD8+ T cells. Conclusions: TLS formation was promoted by CXCL13-producing CD4+ T cells and TLSs facilitated the coordinated antitumor responses of cellular and humoral immunity in ovarian cancer.


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