CAF variants control the tumor-immune microenvironment and predict skin cancer malignancy

Abstract

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. Here, we elucidate the yet unresolved intra-tumoral CAF variety in three skin cancer types at molecular and spatial single-cell resolution in a large cohort. We show that two out of three CAF subtypes contribute to tumor immune surveillance with distinct mechanisms. Matrix CAFs (mCAFs), a previously unknown subtype present in early-stage tumors, ensheath tumor nests and synthesize extracellular-matrix to prevent T cell invasion. Immuno CAFs (iCAFs), which express proinflammatory and immunomodulatory factors, are only detected in high abundance in aggressive tumors. Strikingly, iCAFs but not tumor cells are the exclusive celltype producing chemokines and, thus, play a key role in immune cell recruitment and activation. Mechanistically, we show that cancer cells transform adjacent healthy fibroblasts into cytokine-expressing iCAFs, which subsequently recruit immune cells and modulate the immune response. In conclusion, targeting CAF variants holds promise for improved efficacy of immunotherapy.Statement of significance:While it is accepted that fibroblasts affect cancer progression, the underlying molecular programs remain unclear. We unravel a multi-step cascade demonstrating that tumor cells transform healthy fibroblasts into CAFs, which critically impact immune surveillance via iCAFs being the exclusive source of chemokines and mCAFs promoting T cell exclusion.