scholarly journals The Tumor Immune Landscape and Architecture of Tertiary Lymphoid Structures in Urothelial Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Nick van Dijk ◽  
Alberto Gil-Jimenez ◽  
Karina Silina ◽  
Maurits L. van Montfoort ◽  
Sarah Einerhand ◽  
...  
Keyword(s):  
Clustering Algorithm ◽  
Urothelial Cancer ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cellular Composition ◽  
Comprehensive Overview ◽  
Immune Biomarkers ◽  
Maturation Stages ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

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.

scholarly journals Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Luuk van Hooren ◽  
Alessandra Vaccaro ◽  
Mohanraj Ramachandran ◽  
Konstantinos Vazaios ◽  
Sylwia Libard ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Systemic Delivery ◽  
Systemic Induction ◽  
T Cell Infiltration ◽  
Treatment Naïve ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Immunosuppressive Microenvironment ◽  
The Brain ◽  
Opening Up

AbstractGliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.

scholarly journals Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 155 ◽  
Author(s):  
Martina Gatzka
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Small Molecule ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Metabolic Reprogramming ◽  
Comprehensive Overview ◽  
Small Molecule Drugs ◽  
Mutational Status

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

scholarly journals Agonistic CD40 antibody therapy induces tertiary lymphoid structures but impairs the response to immune checkpoint blockade in glioma

2021 ◽  
Author(s):  
Luuk van Hooren ◽  
Alessandra Vaccaro ◽  
Mohanraj Ramachandran ◽  
Konstantinos Vazaios ◽  
Sylwia Libard ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Immune Checkpoint Blockade ◽  
Cytotoxic T Cell ◽  
Systemic Delivery ◽  
T Cell Infiltration ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

AbstractGliomas are brain tumors characterized by immunosuppression. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors but are yet to be evaluated for glioma. Here, systemic delivery of αCD40 led to cytotoxic T cell dysfunction and impaired the response to immune checkpoint inhibitors in preclinical glioma models. This was associated with an accumulation of suppressive CD11b+ B cells. However, αCD40 also induced tertiary lymphoid structures (TLS). In human glioma, TLS correlated with increased T cell infiltration indicating enhanced immune responses. Our work unveils the pleiotropic effects of αCD40 therapy in glioma, which is of high clinical relevance.

The maturation stage of tumoral tertiary lymphoid structures to predict recurrence risk in localized colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15083-e15083
Author(s):  
Florian Posch ◽  
Karina Silina ◽  
Ulf Petrausch ◽  
Sebastian Leibl ◽  
Axel Muendlein ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Structural Equation ◽  
Critical Role ◽  
Multivariable Analysis ◽  
Recurrence Risk ◽  
Maturation Stage ◽  
Maturation Stages ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

e15083 Background: The tumor immune infiltrate and organized lymphocytic aggregates within the tumor microenvironment, known as tertiary lymphoid structures (TLS), play a critical role in cancer. We hypothesize that the maturation stage of TLS harbors prognostic information on recurrence risk in patients (pts) with non-metastatic colorectal cancer (nmCRC). Methods: In a comprehensive immunofluorescence and clinical analysis of 111 pts with UICC stage II & III nmCRC (median age: 65 yrs; female: n = 53 (48%); stage III: n = 69 (62%)), we quantified the number and maturation status of tumor-associated TLS in baseline surgical specimens:[1] Early TLS (E-TLS, composed of dense lymphocytic aggregates without follicular dendritic cells (FDCs), [2] Primary follicle-like TLS (PFL-TLS, having FDCs but no germinal center (GC) reaction), and [3] Secondary follicle-like TLS (SFL-TLS, having an active GC reaction). The 3-year incidence of recurrence was the primary endpoint of this study, which occurred in 19 pts (3-year recurrence risk = 18.3%). Results: Most TLS formed in tissue adjacent to the tumor. The median number of TLS/mm of tumor perimeter was 1.0 [25th-75th percentile: 0.5-1.7]. The average proportions of different TLS maturation stages were 56% of E-TLS [40-78], 20% of PFL-TLS [6-37], and 16% of SFL-TLS [0-32]. A structural equation model was fitted to summarize the TLS counts and maturation stages into a TLS maturation immunoscore for predicting recurrence. 3-year recurrence risks were 31.7% (95%CI: 17.2-47.3), 15.9% (5.7-30.5), and 9.4% (2.4-22.4) in pts in the 1st, 2nd, and 3rd tertile of the score (Gray’s test p = 0.05). A higher score was significantly associated with a lower recurrence risk (Hazard ratio (HR) for 10 units increase = 0.76, 95%CI: 0.59-0.97, p = 0.03), and this association prevailed in multivariable analysis adjusting for age, ECOG performance status, stage, and adjuvant chemotherapy (Adjusted HR = 0.73, 0.54-0.99, p = 0.05). Conclusions: Tumors of nmCRC pts with a very low risk of recurrence are characterized by an increased fraction of mature TLS comprising FDCs and GCs. If confirmed prospectively, adjuvant chemotherapy may be avoided in nmCRC pts with a high TLS maturation score.

scholarly journals The Immune System of Mesothelioma Patients: A Window of Opportunity for Novel Immunotherapies

2021 ◽  
Author(s):  
Fabio Nicolini ◽  
Massimiliano Mazza
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Cell Types ◽  
Screening Strategies ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Review Current

The interplay between the immune system and the pleural mesothelium is crucial both for the development of malignant pleural mesothelioma (MPM) and for the response of MPM patients to therapy. MPM is heavily infiltrated by several immune cell types which affect the progression of the disease. The presence of organized tertiary lymphoid structures (TLSs) witness the attempt to fight the disease in situ by adaptive immunity which is often suppressed by tumor expressed factors. In rare patients physiological, pharmacological or vaccine-induced immune response is efficient, rendering their plasma a valuable resource of anti-tumor immune cells and molecules. Of particular interest are human antibodies targeting antigens at the tumor cell surface. Here we review current knowledge regarding MPM immune infiltration, MPM immunotherapy and the harnessing of this response to identify novel biologics as biomarkers and therapeutics through innovative screening strategies.

scholarly journals Metagenomic and single-cell RNA-seq survey of the H. pylori-infected stomach in asymptomatic individuals

2021 ◽  
Author(s):  
Chiara Sorini ◽  
Kumar P. Tripathi ◽  
Shengru Wu ◽  
Shawn M. Higdon ◽  
Jing Wang ◽  
...  
Keyword(s):  
Gastric Mucosa ◽  
Single Cell ◽  
Immune Cell ◽  
Human Stomach ◽  
List Type ◽  
Whole Genome ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
H Pylori ◽  
Asymptomatic Individuals

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.

scholarly journals Beyond the Driver Mutation: Immunotherapies in Gastrointestinal Stromal Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Matthieu Roulleaux Dugage ◽  
Robin Lewis Jones ◽  
Jonathan Trent ◽  
Stéphane Champiat ◽  
Sarah Dumont
Keyword(s):  
T Cells ◽  
Gastrointestinal Stromal Tumors ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Growth Factor Receptor ◽  
Driver Mutation ◽  
Cytotoxic T Cell ◽  
Stromal Tumors ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Gastrointestinal stromal tumors (GISTs) are a subtype of soft tissue sarcoma (STS), and have become a concept of oncogenic addiction and targeted therapies.The large majority of these tumors develop after a mutation in KIT or platelet derived growth factor receptor α (PDGFRα), resulting in uncontrolled proliferation. GISTs are highly sensitive to imatinib. GISTs are immune infiltrated tumors with a predominance of tumor-associated macrophages (TAMs) and T-cells, including many CD8+ T-cells, whose numbers are prognostic. The genomic expression profile is that of an inhibited Th1 response and the presence of tertiary lymphoid structures and B cell signatures, which are known as predictive to response to ICI. However, the microtumoral environment has immunosuppressive attributes, with immunosuppressive M2 macrophages, overexpression of indoleamine 2,3-dioxygenase (IDO) or PD-L1, and loss of major histocompatibility complex type 1. In addition to inhibiting the KIT oncogene, imatinib appears to act by promoting cytotoxic T-cell activity, interacting with natural killer cells, and inhibiting the expression of PD-L1. Paradoxically, imatinib also appears to induce M2 polarization of macrophages. There have been few immunotherapy trials with anti-CTLA-4 or anti-PD-L1drugs and available clinical data are not very promising. Based on this comprehensive analysis of TME, we believe three immunotherapeutic strategies must be underlined in GIST. First, patients included in clinical trials must be better selected, based on the identified driver mutation (such as PDGFRα D842V mutation), the presence of tertiary lymphoid structures (TLS) or PD-L1 expression. Moreover, innovative immunotherapeutic agents also provide great interest in GIST, and there is a strong rationale for exploring IDO targeting after disease progression during imatinib therapy. Finally and most importantly, there is a strong rationale to combine of c-kit inhibition with immune checkpoint inhibitors.

scholarly journals Nerve fibers in the Tumor Microenvironment are co-localized with Tertiary Lymphoid Structures

2020 ◽  
Author(s):  
Lara R. Heij ◽  
Xiuxiang Tan ◽  
Jakob N. Kather ◽  
Jan M. Niehues ◽  
Shivan Sivakumar ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cells ◽  
Immune Cell ◽  
Nerve Fibers ◽  
Ductal Adenocarcinoma ◽  
Fiber Density ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Nerve Fiber Density ◽  
Small Nerve

ABSTRACTBackgroundB cells and tertiary lymphoid structures (TLS) are reported to be important in the improvement of survival of cancer patients. These secondary lymphoid organs have been associated with the generation of an anti-tumor response. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types and the stromal architecture shapes the intratumoral heterogeneity. The stroma of PDAC is a complex system in which crosstalk takes place between cancer-associated fibroblasts, immune cells, endothelial cells and the cancer cells. Besides immune cells and fibroblasts, there is some limited data about the influence of nerve fibers on cancer progression.Patients and methodsNerve Fiber Density (NFD) was analysed in our cohort of 188 patients with Pancreatic Ductal Adenocarcinoma who underwent pancreatic surgery. We used immunohistochemistry and multiplex imaging to phenotype the immune cell infiltrate. The cell detection classifier measured distance from immune cell to cancer gland and with a heat map we could count TLS. By using Machine learning we were able to define the spatial distribution and counting Tertiary Lymphoid Structures.ResultsHigh NFD is significantly associated with prolonged overall survival (HR 1.676 (95%CI 1.126,2.495) for low vs. high NFD, p-value 0.0109). The immune cells surrounding the nerve fibers were phenotyped in B cells, T cells and dendritic follicular cells, matching a TLS. Here we show that small nerve fibers are located at the TLS in Pancreatic Cancer and a high Nerve Fiber Density combined with more than 5 TLS is associated with a better survival (HR 0.388 (95%CI 0.218, 0.689).ConclusionThe co-localization of small nerve fibers with TLS is a new finding which has not been described before. However the precise roles of these TLS and nerve fibers remains unknown. These findings unravel future pathways and has the potential to reach new directions into already existing targeted therapy.

scholarly journals Prognostic Significance of Gene Signature of Tertiary Lymphoid Structures in Patients With Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Hong Feng ◽  
Fujun Yang ◽  
Lihong Qiao ◽  
Kai Zhou ◽  
Junfei Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lung Adenocarcinoma ◽  
Immune Cell ◽  
Prognostic Significance ◽  
Gene Signature ◽  
Driver Gene ◽  
Immune Microenvironment ◽  
High Group ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

BackgroundLung adenocarcinoma (LUAD) is a highly mortal cancer. Tertiary lymphoid structures (TLS) are ectopic lymphoid organs with similar morphological and molecular characters to secondary lymphoid organ. The aim of this study is to investigate the prognostic effect of a gene signature associated with TLSs, including B-cell-specific genes.MethodsClinical data of 515 LUAD patients in the TGCA cohort were used to examine the relationship of TLS signature with immune microenvironment, tumor mutational burden (TMB), and driver gene mutations. Patients were divided into the TLS signature high group and TLS signature low group, and comparative analysis of survival and its influencing factors between the two groups was performed. The resulting data were then validated in the GSE37745 cohort.ResultsTLS signature high group had significantly better overall survival (OS) and progression-free interval (PFI) as well as significantly higher infiltration of immune cell subsets, cancer immune cycle (CIC) signature except for immunogram score2 (IGS2), and expression of major checkpoint genes than the TLS signature low group. Notably, while TLS signature was not markedly associated with TMB and mutation frequencies of driver genes, there were significant differences in overall survival of patients with given mutation status of EGFR, KRAS, BRAF and TP53 genes between the TLS signature high and low groups.ConclusionThis study provided evidence that LUAD patients with high TLS signature had a favorable immune microenvironment and better prognosis, suggesting that TLS signature is an independent positive prognostic factor for LUAD patients.

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