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

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. Bulk RNA-seq from mouse PSCs treated with or without TNFa/IFNg for 6 hr