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T cell-mediated development of stromal fibroblasts with an immune-enhancing chemokine profile [single-cell RNA-seq]

ABSTRACT: Stromal fibroblasts reside in inflammatory tissues that are characterized by either immune suppression or activation. Whether and how fibroblasts adapt to these contrasting microenvironments remains unknown. Cancer-associated fibroblasts (CAFs) mediate immune quiescence by producing the chemokine CXCL12, which coats cancer cells to suppress T cell infiltration. We examined whether CAFs can also adopt an immune-promoting chemokine profile. Single-cell RNA-sequencing of CAFs from mouse pancreatic adenocarcinomas identified a sub-population of CAFs with decreased expression of CXCL12 and increased expression of the T cell-attracting chemokine, CXCL9 in association with T cell infiltration. TNFa and IFNg containing conditioned media from activated CD8+ T cells converted stromal fibroblasts from a CXCL12+/CXCL9- immune suppressive phenotype into a CXCL12-/CXCL9+ immune-activating phenotype. Recombinant IFNg and TNFa acted synergistically to induce CXCL9 expression, whereas TNFa alone suppressed CXCL12 expression. This coordinated chemokine switch leads to increased T cell infiltration in an in vitro chemotaxis assay. Our study demonstrates that CAFs have a phenotypic plasticity that allows their adaptation to contrasting immune tissue microenvironments.

ORGANISM(S): Mus musculus

PROVIDER: GSE228836 | GEO | 2023/04/03

REPOSITORIES: GEO

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Project description:Diverse tumour immune phenotypes with distinct T cell infiltration patterns result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these phenotypes remain elusive. Here, we provide a high-resolution dissection of the tumour microenvironment representative of different tumour immune phenotypes. By performing single-cell RNA sequencing (scRNAseq) of the tumour, immune, and stromal compartments from 15 ovarian cancer patients, we characterized the diverse cellular and functional phenotypes, as well as dynamic interplay within and between these components. Infiltrated and excluded tumours markedly differed from desert tumours in several tumour cell intrinsic features, including high interferon response, antigen presentation and oxidative phosphorylation. Moreover, these tumours were characterized by tumour associated macrophage (TAM)-like myeloid subsets, while desert tumours were enriched in myeloid derived suppressive cell (MDSC)-like myeloid subsets. Infiltrated and excluded tumours differed in their T cell composition and fibroblast subsets. While dysfunctional CD8+ GZMB T cells and IL1-activated fibroblasts (IL1 CAFs) were associated with infiltrated tumours, pre-dysfunctional CD8+ GZMK T cells and TGFB-activated fibroblasts (TGFB CAFs) were enriched in excluded tumours. These findings validated in bulk transcriptomic profiles of 1071 ovarian tumours and using in situ hybridization. Furthermore, our study revealed chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumour cell-T cell crosstalk via a CXC16-CXCR6 axis, stromal-immune cell crosstalk via CXCL12/14-CXCR4 signalling, and TAM-like macrophage-T cell crosstalk through CXCR3-CXCL9/10/11 signalling. Our in-depth characterization of the tumour environment and intercellular interactions provides novel insights into potential molecular mechanisms that shape the distinct biology of tumour immune phenotypes. Our findings may inform novel therapeutic strategies for potentially shifting tumours along the immunity continuum to improve clinical benefit from cancer immunotherapies.

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T cell-mediated development of stromal fibroblasts with an immune-enhancing chemokine profile [single-cell RNA-seq]

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