RETRACTED: Cancer-Associated Fibroblasts-Derived Exosomes Suppress Immune Cell Function in Breast Cancer via the miR-92/PD-L1 Pathway

Abstract

Cancer-associated fibroblasts (CAFs) are an essential component in the tumor microenvironment and have been reported to contribute to tumor progression through many mechanisms; however, the detailed mechanism underlying the immune-suppression effect of CAFs is not clearly defined. In this study, human breast cancer-derived CAFs were cultured, and CAF-derived exosomes in a culture medium were isolated. Using a miRNA profiles assay, we identify a significantly higher level of microRNA-92 isolated in CAFs exosomes. After treatment by CAF-derived exosomes, breast cancer cells express higher programmed cell death receptor ligand 1 (PD-L1), accompanied with increased miR-92 expression. Increased PD-L1 expression, which was induced by CAF-derived exosomes, significantly promotes apoptosis and impaired proliferation of T cells. The underlying mechanism of this effect was studied, proliferation and migration of breast cancer cells were increased after the transfection of miR-92, LATS2 was recognized as a target gene of miR-92, and further confirmed by a luciferase assay. Immunoprecipitation showed that LATS2 can interact with YAP1, chromatin immunoprecipitation confirmed that after nuclear translocation YAP1 could bind to the enhancer region of PD-L1 to promotes transcription activity. Furthermore, the animal study confirmed that CAFs significantly promoted tumor progression and impaired the function of tumor-infiltrated immune cells in vivo . Our data revealed a novel mechanism that can induce immune suppression in the tumor microenvironment.

Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy

“…Consequently, PD-L1/2 expression in the TME promotes immunosuppression, protecting cancer cells from T cell-mediated killing, and thus has become an important target for checkpoint inhibition. Fibroblasts within the TME can express PD-L1/2 themselves ( Pinchuk et al, 2008 ; Nazareth et al, 2007 ; Cho et al, 2011 ) as well as increase PD-L1/2 expression in tumor cells via CXCL5 signaling ( Li et al, 2019 )—as shown in melanoma and CRC—or miR-92 delivered via CAF-derived exosomes—as shown in breast cancer ( Dou et al, 2020 ).…”

Exosomes in Immune Regulation

“…Finally, tumor formation was promoted in xenografted nude mice. A significantly high level of miR-92 in ExVs of cancer-associated fibroblasts [CAFs] was detected in breast cancer by Dou et al [ 66 ]. Following treatment by CAF-derived ExVs, breast cancer cells expressed higher levels of PD-L1, accompanied with increased miR-92 expression.…”

Clinical Implications of Exosomal PD-L1 in Cancer Immunotherapy

“…Current studies demonstrate that CAFs from a variety of tumor types release an array of factors that increase PD-L1 expression in tumor cells [ 84 , 85 ]. Evidence suggests that TGF- β 1, which is also found in CAF-derived exosomes, upregulates PD-L1 expression in a Smad2-dependent manner in NSCLC cells [ 86 , 87 ].…”

“…CAFs secrete CXCL2 and CXCL5 which induce PD-L1 expression in tumor cells via JAK/STAT and PI3K/AKT signaling, respectively [ 82 , 85 ]. These findings suggest that CAF-derived soluble factors upregulate PD-L1 expression in tumor cells by activating signaling pathways that have also been associated with exosomal PD-L1 release [ 84 , 88 , 89 ].…”