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Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs.

ABSTRACT: Innate lymphoid cells (ILCs) have been classified into "functional subsets" according to their transcription factor and cytokine profiles. Although cytokines, such as IL-12 and IL-23, have been shown to shape plasticity of ILCs, little is known about how the tissue microenvironment influences the plasticity, phenotype, and function of these cells. Here, we show clearly demarcated tissue specifications of Rorc-dependent ILCs across lymphoid and nonlymphoid organs. Although intestinal Rorc fate map-positive (Rorc^fm+) ILCs show a clear ILC3 phenotype, lymphoid tissue-derived Rorc^fm+ ILCs acquire an natural killer (NK) cell/ILC1-like phenotype. By adoptively transferring Rorc^fm+ ILCs into recipient mice, we show that ILCs distribute among various organs and phenotypically adapt to the tissue environment they invade. When investigating their functional properties, we found that only lymphoid-tissue resident Rorc^fm+ ILCs can suppress tumor growth, whereas intestinal Rorc^fm- ILC1s or NK cells fail to inhibit tumor progression. We thus propose that the tissue microenvironment, combined with ontogeny, provides the specific function, whereas the phenotype is insufficient to predict the functional properties of ILCs.

SUBMITTER: Nussbaum K

PROVIDER: S-EPMC5551572 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs.

Nussbaum Kathrin K Burkhard Sara H SH Ohs Isabel I Mair Florian F Klose Christoph S N CSN Arnold Sebastian J SJ Diefenbach Andreas A Tugues Sonia S Becher Burkhard B

The Journal of experimental medicine 20170711 8

Innate lymphoid cells (ILCs) have been classified into "functional subsets" according to their transcription factor and cytokine profiles. Although cytokines, such as IL-12 and IL-23, have been shown to shape plasticity of ILCs, little is known about how the tissue microenvironment influences the plasticity, phenotype, and function of these cells. Here, we show clearly demarcated tissue specifications of <i>Rorc</i>-dependent ILCs across lymphoid and nonlymphoid organs. Although intestinal <i>Ro ...[more]

PMID: 28698286

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Project description:The core Hippo pathway module consists of a tumour-suppressive kinase cascade that inhibits the transcriptional coactivators Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ). When the Hippo pathway is downregulated, as often occurs in breast cancer, YAP/TAZ activity is induced. To elaborate the roles of TAZ in triple-negative breast cancer (TNBC), we depleted Taz in murine TNBC 4T1 cells, using either CRISPR/Cas9 or small hairpin RNA (shRNA). TAZ-depleted cells and their controls, harbouring wild-type levels of TAZ, were orthotopically injected into the mammary fat pads of syngeneic BALB/c female mice, and mice were monitored for tumour growth. TAZ depletion resulted in smaller tumours compared to the tumours generated by control cells, in line with the notion that TAZ functions as an oncogene in breast cancer. Tumours, as well as their corresponding in vitro cultured cells, were then subjected to gene expression profiling by RNA sequencing (RNA-seq). Interestingly, pathway analysis of the RNA-seq data indicated a TAZ-dependent enrichment of 'Inflammatory Response', a pathway correlated with TAZ expression levels also in human breast cancer tumours. Specifically, the RNA-seq analysis predicted a significant depletion of regulatory T cells (Tregs) in TAZ-deficient tumours, which was experimentally validated by the staining of tumour sections and by quantitative cytometry by time of flight (CyTOF). Strikingly, the differences in tumour size were completely abolished in immune-deficient mice, demonstrating that the immune-modulatory capacity of TAZ is critical for its oncogenic activity in this setting. Cytokine array analysis of conditioned medium from cultured cells revealed that TAZ increased the abundance of a small group of cytokines, including plasminogen activator inhibitor 1 (Serpin E1; also known as PAI-1), CCN family member 4 (CCN4; also known as WISP-1) and interleukin-23 (IL-23), suggesting a potential mechanistic explanation for its in vivo immunomodulatory effect. Together, our results imply that TAZ functions in a non-cell-autonomous manner to modify the tumour immune microenvironment and dampen the anti-tumour immune response, thereby facilitating tumour growth.

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Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs.

Publications

Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs.

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