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.
Background Under certain stress conditions, such as oxidative stress or nutrient deprivation, specific RNA-binding proteins aggregate with actively translated mRNAs to facilitate translational reprogramming and cell survival. 1 High levels or deregulated activity of these RNA-binding proteins, which include Ras GTPase-activating protein-binding protein 1 (G3BP1) or Y-box-binding protein 1 (YB-1) contribute to tumour progression and metastasis. 2 Inhibition of stress granule (SG) formation may therefore exert a synergistic effect with cytotoxic chemotherapy. Materials and Methods Formalin-fixed paraffin-embedded sections from neoadjuvant-treated colorectal cancer (CRC) liver metastasis patients (n=33) were immunohistochemically (IHC) stained for YB-1. CRC cell-lines as well as organoids and tissue slice cultures from surgical specimen were treated with oxaliplatin/5-fluorouracil alone or in combination with the histone deacetylase inhibitor (HDACi) MS-275. Incubation with arsenic acid served as positive control for SG aggregation. Immunofluorescence co-staining of YB-1 and G3BP1 was used to detect SG formation. Cell viability and apoptosis induction were analysed using viability (cellular adenosine triphosphate) and cytotoxicity (lactate-dehydrogenase release) assays, flowcytometry (active caspase 3, viability dye) and IHC (haematoxylin & eosin, active caspase 3, Ki-67). Results In the cohort of CRC liver metastasis patients, YB-1 protein expression was a negative predictor for overall survival. Oxaliplatin-based chemotherapy induced SG formation in CRC cell-lines and primary tumour tissue culture. Pre-treatment with the HDACi MS-275 prevented stress-granule aggregation and increased the sensitivity of CRC cell lines to oxaliplatin. Conclusions Clinical data and CRC cell-line or primary tissue cultures identify SG formation as a resistance factor for chemotherapy and as a therapeutic target in CRC.
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