Dataset Information

Immunoproteomics of Lymph Node T-cells in Bladder Cancer

ABSTRACT: The immune-suppressive features often possessed by invasive tumors hamper effective anti-tumor immunity. In this context, tumor-infiltrating regulatory T cells (Tregs) have been widely implied, principally as unwanted suppressors of anti-tumor immune responses. However, while many studies have focused on tumor-infiltrating Tregs, the function and signaling of Tregs in tumor-associated lymph nodes is largely unknown. In this study, we set out to clarify how immune signaling in lymph nodes is impacted by its contact to the tumour. Because muscle-invasive urothelial bladder cancer (MIBC) represent an immunogenic cancer were Tregs are accumulated and sentinel nodes (SNs) can be efficiently detected, we explored the protein expression of T-cells in SNs and non-SNs of MIBC patients. Proteomic analysis of Tregs and effector T-cells in SN and non-draining lymph nodes found SN-Tregs in MIBC patients to up-regulate growth and immune signaling pathways, the cytokine IL-16 being central in the signaling network. Experimental validation showed that in Tregs, tumoral factors increase IL-16 processing into bioactive forms and increase FOXP3 expression. In conclusion, altered IL-16 processing caused by tumour-released factors stimulate expansion of SN-Tregs in MIBC, creating an immunosuppressive environment and contributing to immune escape.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Lymph Node, Blood

SUBMITTER: Michael Mints

LAB HEAD: Ola Winqvist

PROVIDER: PXD009569 | Pride | 2020-09-09

REPOSITORIES: Pride

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Publications

IL-16 processing in sentinel node regulatory T cells is a factor in bladder cancer immunity.

Krantz David D Mints Michael M Winerdal Malin M Riklund Katrine K Rutishauser Dorothea D Zubarev Roman R Zirakhzadeh Amir Ali AA Alamdari Farhood F Johansson Markus M Sherif Amir A Winqvist Ola O

Scandinavian journal of immunology 20200830 6

In the effort of developing new immunotherapies, the sentinel node (SN) has proven a promising source from which to harness an effective antitumour T cell response. However, tumour immune escape, a process in which regulatory T cells (Tregs) play a central role, remains a major limiting factor. Therefore, there is a clear need to increase the knowledge of Treg function and signalling in sentinel nodes. Here, we set out to explore whether the proteome in SN-resident T cells is altered by the tumo ...[more]

PMID: 32862475

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Project description:The goal of the study was to identify the genes which are regulated by Interleukin-2 in the CD4+ T cells of the scurfy mice during regulatory T-cell deficiency. Scurfy (Sf) mice bear a mutation in the forkhead box P3 (Foxp3) transcription factor, lack regulatory T-cells (Treg), develop multi-organ inflammation, and die prematurely. The major target organs affected are skin, lungs, and liver. Sf mice lacking the Il2 gene (Sf.Il2-/-), despite devoid of Treg, did not develop skin and lung inflammation, but the inflammation in liver, pancreas, submandibular gland and colon remained. Genome-wide microarray analysis revealed hundreds of genes were differentially regulated among Sf, Sf.Il2-/-, and B6 CD4+ T-cells but the most changes were those encoding receptors for trafficking/chemotaxis/retention and lymphokines. Our study suggests that IL-2 controls the skin and lung inflammation in Sf mice in an apparent "organ-specific" manner through two novel mechanisms: by regulating the expression of genes encoding receptors for T-cell trafficking/chemotaxis/retention and by regulating Th2 cell expansion and lymphokine production. Thus, IL-2 is a master regulator for multi-organ inflammation and an underlying etiological factor for various diseases associated with skin and lung inflammation. Methods: CD4+ T cells were purified by Fluorescence Assisted Cell Sorting from the peripheral lymph nodes of (A) three individual Scurfy (Sf; B6.Cg-Foxp3sf/J) male mice, (B) three individual Sf.Il2-/- male mice (Scurfy mice carrying a null Interleukin (IL)-2 gene (B6.129P2-Il2tm1Hor/J)) and (C) a pooled sample of lymph nodes from two B6 (C57BL/6J) mice. All the mice were 3 weeks old. Total RNA was prepared using RNeasy mini kit (Qiagen). RNA samples were converted to cRNA, labeled and hybridized to Affymetrix Mouse 430_2 chips (Mouse Genome 430 2.0 Array, Affymetrix, Santa Clara, CA) at the University of Virginia DNA Sciences Core Facility. 1. RNA from CD4+ T cells purified from pooled peripheral lymph nodes of two 3-week old B6 mice) - 1 biological replicate 2. RNA from CD4+ T-cells purified from peripheral lymph nodes of 3-week old scurfy (Sf) mice - 3 biological replicates. 3. RNA from CD4+ T cells purified from peripheral lymph nodes of Sf.Il2-/- mice - 3 biological replicates.

Dataset Information

Immunoproteomics of Lymph Node T-cells in Bladder Cancer

Publications

IL-16 processing in sentinel node regulatory T cells is a factor in bladder cancer immunity.

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