scholarly journals The 12-CK Score: Global Measurement of Tertiary Lymphoid Structures

2021 ◽  
Vol 12 ◽  
Author(s):  
Roger Li ◽  
Anders Berglund ◽  
Logan Zemp ◽  
Jasreman Dhillon ◽  
Ryan Putney ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Predictive Marker ◽  
Immune Checkpoint Blockade ◽  
Lymphoid Organ ◽  
Predictors Of Response ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Tumor Types ◽  
Anti Tumor Activity ◽  
Lymphoid Aggregates

There is emerging evidence that the adaptive anti-tumor activity may be orchestrated by secondary lymphoid organ-like aggregates residing in the tumor microenvironment. Known as tertiary lymphoid structures, these lymphoid aggregates serve as key outposts for lymphocyte recruitment, priming and activation. They have been linked to favorable outcomes in many tumor types, and more recently, have been shown to be effective predictors of response to immune checkpoint blockade. We have previously described a 12-chemokine (12-CK) transcriptional score which recapitulates an overwhelming enrichment for immune-related and inflammation-related genes in colorectal carcinoma. Subsequently, the 12-CK score was found to prognosticate favorable survival in multiple tumors types including melanoma, breast cancer, and bladder cancer. In the current study, we summarize the discovery and validation of the 12-CK score in various tumor types, its relationship to TLSs found within the tumor microenvironment, and explore its potential role as both a prognostic and predictive marker in the treatment of various cancers.

Mature tertiary lymphoid structures in lung adenocarcinoma are associated with better progression free survival

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S149-S149
Author(s):  
R Obeng ◽  
V Parihar ◽  
D Alexis ◽  
M Behera ◽  
T Owonikoko ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Progression Free Survival ◽  
Germinal Centers ◽  
Disease Stage ◽  
Free Survival ◽  
Formalin Fixed Paraffin Embedded ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Lymphoid Aggregates

Abstract Introduction/Objective The presence of inducible lymphoid structures known as tertiary lymphoid structures in the tumor microenvironment has been shown to correlate with positive clinical outcome. However, the maturation states of lymphoid aggregates in lung adenocarcinoma are not completely understood. Methods/Case Report Seventy tumor samples from 69 patients diagnosed with lung adenocarcinoma (Stages I to III) between 2013 and 2015 were included in the study. The presence and maturation states of the lymphoid structures within the tumors were evaluated by conventional and 26 samples were further analyzed by multiplexed immunohistochemistry of formalin fixed paraffin embedded tissues and then quantified. Mature lymphoid follicles containing germinal centers were identified by the presence of CD21+ and BCL-6+ cells in an organized configuration within tight clusters of T and B cells. Results (if a Case Study enter NA) Samples with fully mature lymphoid structures (germinal centers) had larger tumors and higher disease stage. The number of mature lymphoid structures correlated with the total number of lymphoid aggregates present in the tumor microenvironment. Additionally, tumor samples with ≥10 mature lymphoid structures had more primary follicles. While there was no difference in overall survival, progression free survival was significantly longer in patients who had ≥10 mature lymphoid structures in comparison with patients who had <10 mature structures. Conclusion In conclusion, a spectrum of lymphoid aggregates in different stages of maturation are present in lung adenocarcinoma. An increase in the number of mature lymphoid structures may be associated with progression free survival in patients with lung adenocarcinoma.

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.

scholarly journals Lymphoid aggregates in desmoplastic melanoma have features of tertiary lymphoid structures

2018 ◽  
Vol 28 (3) ◽  
pp. 237-245 ◽  
Author(s):  
Anne M. Stowman ◽  
Alexandra W. Hickman ◽  
Ileana S. Mauldin ◽  
Adela Mahmutovic ◽  
Alejandro A. Gru ◽  
...  
Keyword(s):  
Desmoplastic Melanoma ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Lymphoid Aggregates

scholarly journals Therapeutic Induction of Tertiary Lymphoid Structures in Cancer Through Stromal Remodeling

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna Johansson-Percival ◽  
Ruth Ganss
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Tumor Rejection ◽  
Cell Infiltration ◽  
Cytotoxic T Cell ◽  
T Cell Infiltration ◽  
Anti Cancer ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Improving the effectiveness of anti-cancer immunotherapy remains a major clinical challenge. Cytotoxic T cell infiltration is crucial for immune-mediated tumor rejection, however, the suppressive tumor microenvironment impedes their recruitment, activation, maturation and function. Nevertheless, solid tumors can harbor specialized lymph node vasculature and immune cell clusters that are organized into tertiary lymphoid structures (TLS). These TLS support naïve T cell infiltration and intratumoral priming. In many human cancers, their presence is a positive prognostic factor, and importantly, predictive for responsiveness to immune checkpoint blockade. Thus, therapeutic induction of TLS is an attractive concept to boost anti-cancer immunotherapy. However, our understanding of how cancer-associated TLS could be initiated is rudimentary. Exciting new reagents which induce TLS in preclinical cancer models provide mechanistic insights into the exquisite stromal orchestration of TLS formation, a process often associated with a more functional or “normalized” tumor vasculature and fueled by LIGHT/LTα/LTβ, TNFα and CC/CXC chemokine signaling. These emerging insights provide innovative opportunities to induce and shape TLS in the tumor microenvironment to improve immunotherapies.

scholarly journals Tertiary lymphoid structures induced by CXCL13-producing CD4+ T cells increase tumor infiltrating CD8+ T cells and B cells in ovarian cancer

2021 ◽  
Author(s):  
Masayo Ukita ◽  
Junzo Hamanishi ◽  
Hiroyuki Yoshitomi ◽  
Koji Yamanoi ◽  
Shiro Takamatsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
T Cells ◽  
B Cells ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
Tumor Infiltrating Lymphocytes ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

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.

scholarly journals TAMI-51. IDENTIFYING NEW TUMOR MICROENVIRONMENT (TME) CONTEXTS OF VULNERABILITY IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii224-ii224
Author(s):  
Kieron White ◽  
Maxime Meylan ◽  
Antoine Bougoüin ◽  
Kate Connor ◽  
Manuela Salvucci ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Treatment Strategies ◽  
Adult Brain ◽  
Significant Difference ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
High Level ◽  
Checkpoint Genes ◽  
Rna Signature

Abstract Glioblastoma (GBM) is the most frequent and aggressive adult brain tumor with 85% of patients dying within two years. New effective precision medicine therapies are urgently required, especially for isocitrate dehydrogenase wild-type (IDHwt) disease. Despite efforts to subtype patients based on molecular profiles, this approach has yet failed to direct treatment strategies. Further interrogation of the tumor microenvironment (TME) across molecular subtypes and identification of new TME specific subtypes may guide new directions for future therapies. Here, we analysed transcriptomic data from selected GLIOTRAIN(www.gliotrain.eu)(n=120) and TCGA(n=69) IDHwt patients. Firstly, the microenvironment cell population (MCP)-counter method (a gene-expression-based TME deconvolution tool) was validated for use in the brain tumor setting using quantitative multiplex immunohistochemistry. In this context, immune markers (CD20/CD3/CD68/CD8) were significantly correlated with MCP-counter scores. We are currently optimizing and validating a vessel-density and microglial RNA-signature to provide a more robust representation of brain TME. Next, using MCP-counter, the TME composition of IDHwt tumors was assessed within proneural (24%), classical (38%) and mesenchymal (38%) subtypes. We initially classified the GLIOTRAIN cohort into 3 novel clusters characterised by differences in TME composition and validated our findings in the TCGA cohort. A TME-high group (37%) is characterized by elevated presence of lymphocytes and myeloid cells, and presents a high level of immune checkpoint genes: PDCD1(PD1) and CTLA4. In addition, the presence of tertiary lymphoid structures (TLS) is a feature of TMEhigh/mesenchymal+ patients. This finding has been validated by IHC and RNA-signature. TME-med (38%) displayed heterogenous immune populations and the TME-low (25%) represented an ‘immune-desert’ group. There was no significant difference in OS based on these TME subtypes(p=0.50). We hypothesise that PD1/CTLA4 blockade might be an effective treatment strategy in TME-high patients. These hypotheses will be tested (in the adjuvant setting) using appropriate syngeneic disease models which incorporate surgical resection.

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