Tissue resident-like CD8 T cells link neo-antigen load to tertiary lymphoid structures in endometrial cancer

2020 ◽  
Vol 159 ◽  
pp. 337
Author(s):  
J. Lubbers ◽  
M. Wazynska ◽  
N. van Rooij ◽  
M. de Bruyn ◽  
H. Nijman
Keyword(s):  
T Cells ◽  
Endometrial Cancer ◽  
Cd8 T Cells ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

scholarly journals TGF-β induced CXCL13 in CD8+ T cells is associated with tertiary lymphoid structures in cancer

2018 ◽  
Author(s):  
HH Workel ◽  
JM Lubbers ◽  
R Arnold ◽  
T Prins ◽  
P van der Vlies ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Human Tumors ◽  
Unexpected Finding ◽  
Follicular Helper ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

AbstractCoordinated immune responses against human tumors are frequently characterized by tertiary lymphoid structures (TLS) which predict improved prognosis. The development of TLS is dependent on the chemokine CXCL13, reported to be secreted by dendritic cells and follicular helper T cells only. We report the unexpected finding that CXCL13 is also secreted by activated CD8+ T cells following stimulation by transforming growth factor beta (TGF-β). Using single cell RNA sequencing we found that expression ofCXCL13in CD8+ T cells was restricted to the intraepithelial CD103+ population. Accordingly, CD8+ T cells activated in the presence of TGF-β simultaneously upregulated CD103 and secreted CXCL13.CXCL13expression was strongly correlated with neo-antigen burden and cytolytic gene signatures in bulk tumors. In line with this, TLS were abundant in neo-antigen-high, CD103+ T cell-enriched tumors. TGF-β thus appears to play a role in coordinating immune responses against human tumors through CD8-dependent CXCL13-associated formation of TLS.

scholarly journals CD8+ T cells located in tertiary lymphoid structures are associated with improved prognosis in patients with gastric cancer

2020 ◽  
Vol 20 (3) ◽  
pp. 2655-2664
Author(s):  
Qing Li ◽  
Dachuan Zhang ◽  
Wenting He ◽  
Tongbing Chen ◽  
Zhantao Yan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Cd8 T Cells ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Predictive biomarkers for response to nivolumab in head and neck squamous cell carcinoma (HNSCC) (NCT#03652142).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6060-6060
Author(s):  
Amanda Psyrri ◽  
Niki Gavrielatou ◽  
Aris Spathis ◽  
Maria Anastasiou ◽  
Ekaterina Fortis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Cd8 T Cell ◽  
Post Treatment ◽  
Tertiary Lymphoid Structures ◽  
Pre Treatment ◽  
Lymphoid Structures

6060 Background: Tumor immune cell compositions determine response to immunotherapy. For a better understanding of the mechanisms of resistance to nivolumab in HNSCC, we sought to investigate a prospective cohort of longitudinal HNSCC samples from recurrent/metastatic HNSCC pts treated with nivolumab and identify biomarkers of response and resistance. We will specifically focus on modulation of immune markers following two cycles of nivolumab. Methods: Patients with platinum-refractory HNSCC with no contraindication to nivolumab therapy are included in this study. Tumor biopsies are performed at baseline, 24-72 hours after the second cycle and at progression with appropriate written informed consent. Samples were assessed for the presence of Tertiary Lymphoid Structures (TLS), PD-L1 expression (TPS and CPS) and CD8 T cell infiltrates combined with Ki67 (CD8/Ki67 double IHC stain). The primary outcome measure of the study is change in the percentage of immune cells in post treatment compared to baseline biopsies. Secondary endpoints include safety of performing a second biopsy, best overall response rate, biomarker expression in association with response and survival. Evaluation of other biomarkers including tumor mutational burden, HLA class I and II expression and adaptive immunity cell populations using multiplex IF is ongoing. Results: Of 20 patients evaluable for response, 14 had PD (8 of whom showed hyper-progression) and 6 attained disease control (1 with PR). PD-L1 status (CPS or TPS) was not altered by treatment (p = 0.905) and CPS > 20 pre-treatment showed a favorable trend towards response (p = 0.117). Absence of tertiary lymphoid structures was associated with disease progression (p = 0.0374). Infiltrating plasma cell count remained unchanged pre- and post-treatment and was unrelated to response (p = 0.458). The percentage of proliferating CD8+ T cells (CD8+/Ki67+) increased in post-treatment biopsies in the entire population (p = 0.022) and especially in progressors (p = 0.039). Pre-treatment CD8+ T cell density was higher in patients with hyper-progression compared to progressors (p = 0.029). Conclusions: Increased percentage of proliferating CD8+ T cells in progressors might represent dysfunctional T cells as has been recently shown in melanoma pts (Li H et al Cell 2019) and clinical efforts to reactivate intratumoral T cells may augment the efficacy of PD1 checkpoint inhibitors. Clinical trial information: NCT03652142.

scholarly journals Tertiary Lymphoid Structures as a Predictive Biomarker of Response to Cancer Immunotherapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Trüb ◽  
Alfred Zippelius
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Tumour Response ◽  
Predictive Biomarker ◽  
Exciting Field ◽  
Inflammatory Conditions ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Cancer Immunotherapies

Tertiary lymphoid structures (TLS) are ectopic lymphoid formations which are formed under long-lasting inflammatory conditions, including tumours. TLS are composed predominantly of B cells, T cells and dendritic cells, and display various levels of organisation, from locally concentrated aggregates of immune cells, through clearly defined B cell follicles to mature follicles containing germinal centres. Their presence has been strongly associated with improved survival and clinical outcome upon cancer immunotherapies for patients with solid tumours, indicating potential for TLS to be used as a prognostic and predictive factor. Although signals involved in TLS generation and main cellular components of TLS have been extensively characterised, the exact mechanism by which TLS contribute to the anti-tumour response remain unclear. Here, we summarise the most recent development in our understanding of their role in cancer and in particular in the response to cancer immunotherapy. Deciphering the relationship between B cells and T cells found in TLS is a highly exciting field of investigation, with the potential to lead to novel, B-cell focused immunotherapies.

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 The relationship of the tertiary lymphoid structures with the tumor-infiltrating lymphocytes and its prognostic value in gastric cancer

2021 ◽  
Author(s):  
Nana Zhang ◽  
Guanjun Zhang ◽  
Depu Wang ◽  
Hao Liu ◽  
Yuchi Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Prognostic Value ◽  
Tumor Infiltrating Lymphocytes ◽  
High Endothelial Venules ◽  
Tumor Center ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Infiltrating Lymphocytes ◽  
The Relationship

IntroductionTo explore the relationship between the tertiary lymphoid structures (TLSs) and tumor-infiltrating lymphocytes (TILs), and their distribution characteristics as well as the prognostic value in gastric cancer (GC).Material and methodsThe TLSs and four subtypes of TILs were assessed by immunohistochemistry (IHC) staining. The presence of MECA-79 positive high endothelial venules (HEVs) identified among the ectopic lymphocyte aggregation area in the GC tissue was defined as a valid TLSs.The number of labeled TILs were observed in 5 fields of the most positive cells in tumor center, invasive edge and within the TLSs, respectively, at a field of vision×40.ResultsThe TLSs distributed significantly higher in the tumor invasive edge than the tumor center (P <0.001). Similarly, the infiltrating density of CD8+T cells and GrB+T cells were highly distributed in the tumor infiltrating edge than the tumor center. While the total number of TILs and the FOXP3+T cells were on the contrary. There was a positive correlation between the density of TLSs and TILs either in the location or the immune phenotype. And a higher frequency of TILs and TLSs often associated with the favorable clinicopathologic parameters. Multivariate analysis revealed that the density of TILs (P= 0.019) and TLSs (P= 0.037) were the independent prognostic predictor for GC patients.ConclusionsThe formation of TLSs predicts an advantageous immune system function and can be considered as a novel biomarker to stratify the overall survival risk of untreated GC patients and as a marker of efficient immunotherapies.

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