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

Workel, Hagma H.; Lubbers, Joyce M.; Arnold, Roland; Prins, Thalina M.; Vlies, Pieter van der; Lange, Katrin; Bosse, Tjalling; Gool, Inge C. van; Eggink, Florine A.; Wouters, Maartje C.A.; Komdeur, Fenne L.; Creutzberg, Carien L.; Kol, Arjan; Plat, Annechien; Glaire, Mark A.; Church, David N.; Nijman, Hans W.; Bruyn, Marco de

doi:10.1101/303834

Cited by 2 publications

(2 citation statements)

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“…MMRp cases lacking pathogenic POLE mutation or p53 abnormality/mutation were assigned to the NSMP category. Methods used to determine additional molecular factors have been reported previously [11,15] CD8 and CD103 immunostaining Tissue microarrays (TMA) of the PORTEC-1 and PORTEC-2 trials were produced as previously described [3,4] Dual marker immunohistochemistry was performed using a modification of a previously published protocol [29] as follows. FFPE slides were deparaffinized and rehydrated in graded ethanol.…”

Section: Determination Of Molecular Subgroups and Other Molecular Facmentioning

confidence: 99%

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Horeweg

Bruyn

Nout

et al. 2020

Cancer Immunology Research

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Optimum risk stratification in early-stage endometrial cancer (EC) combines clinicopathological factors and the molecular EC classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning image-based algorithm to quantify density of CD8 + and CD103 + immune cells in tumor epithelium and stroma in 695 stage I endometrioid ECs from the PORTEC-1&-2 trials. The relationship between immune cell density and clinicopathological/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular EC classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate and low densities, with highly significant variation in the proportion of molecular EC subgroups between them. Univariable analysis revealed intraepithelial CD8 + cell density as the strongest predictor of EC recurrence; multivariable analysis confirmed this was independent of pathological factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair deficient cancers. Thus, this work identified that quantification of intraepithelial CD8 + cells improved upon the prognostic utility of the molecular EC classification in early-stage EC.

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Section: Determination Of Molecular Subgroups and Other Molecular Facmentioning

confidence: 99%

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Horeweg

Bruyn

Nout

et al. 2020

Cancer Immunology Research

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“…While most CXCL13 + T cells in breast cancer samples are CD4 + T cells, a subset of tumor-infiltrating CD8 + T cells was also noted to produce CXCL13 and reside near B cell follicles, albeit with lower CXCL13 expression than in CD4 + T cells [ 105 ]. CXCL13 expression has also been observed in CD103 + CD8 + T cells in ovarian cancer tumors [ 117 ]. It will be interest to evaluate further the relative contributions, and functional overlap, of CD4 + and CD8 + T cells that produce CXCL13.…”

Section: Cxcl13-producing T Cells In Inflamed Tissuesmentioning

confidence: 99%

T Cells That Help B Cells in Chronically Inflamed Tissues

2018

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Chronically inflamed tissues commonly accrue lymphocyte aggregates that facilitate local T cell-B cell interactions. These aggregates can range from small, loosely arranged lymphocyte clusters to large, organized ectopic lymphoid structures. In some cases, ectopic lymphoid structures develop germinal centers that house prototypical T follicular helper (Tfh) cells with high expression of Bcl6, CXCR5, PD-1, and ICOS. However, in many chronically inflamed tissues, the T cells that interact with B cells show substantial differences from Tfh cells in their surface phenotypes, migratory capacity, and transcriptional regulation. This review discusses observations from multiple diseases and models in which tissue-infiltrating T cells produce factors associated with B cell help, including IL-21 and the B cell chemoattractant CXCL13, yet vary dramatically in their resemblance to Tfh cells. Particular attention is given to the PD-1hi CXCR5− Bcl6low T peripheral helper (Tph) cell population in rheumatoid arthritis, which infiltrates inflamed synovium through expression of chemokine receptors such as CCR2 and augments synovial B cell responses via CXCL13 and IL-21. The factors that regulate CD4+ T cell production of CXCL13 and IL-21 in these settings are also discussed. Understanding the range of T cell populations that can provide help to B cells within chronically inflamed tissues is essential to recognize these cells in diverse inflammatory conditions and to optimize either broad or selective therapeutic targeting of B cell-helper T cells.

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

Cited by 2 publications

References 52 publications

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

T Cells That Help B Cells in Chronically Inflamed Tissues

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