The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy

Abstract

Fibroblasts are a key component of the tumor microenvironment (TME) that can serve as a scaffold for tumor cell migration and augment the tumor's ability to withstand harsh conditions. When activated by external or endogenous stimuli, normal fibroblasts become cancer associated fibroblasts (CAFs), a heterogeneous group of stromal cells in the tumor that are phenotypically and epigenetically different from normal fibroblasts. Dynamic crosstalk between cancer cells, immune cells, and CAFs through chemokines and surface signaling makes the TME conducive to tumor growth. When activated, CAFs promote tumorigenesis and metastasis through several phenomena including regulation of tumor immunity, metabolic reprogramming of the TME, extracellular matrix remodeling and contraction, and induction of therapeutic resistance.Ionizing radiation (radiation theraphy [RT]) is a potent immunological stimulant that has been shown to increase cytotoxic Teff infiltration and IFN-I stimulated genes. RT, however, is unable to overcome the infiltration and activation of immunosuppressive cells which can contribute to tumor progression. Another paradox of RT is that, while very effective at killing cancer cells, it can contribute to the formation of CAFs. This review examines how the interplay between CAFs and immune cells during RT contributes to organ fibrosis, immunosuppression, and tumor growth. We focus on targeting mechanistic pathways of CAF formation as a potentially effective strategy not only for preventing organ fibrosis, but also in hampering tumor progression in response to RT. K E Y W O R D Scancer associated fibroblast, immune microenvironment, immunotherapy, radiation therapy

Advanced co-culture 3D breast cancer model for investigation of fibrosis induced by external stimuli: optimization study

“…In general, our data suggest that spheroids generated after sequential seeding of fibroblasts in 1:3 ratio to the already formed MCF-7 aggregates (1000 cells/per well) were optimal for further investigation of fibrotic reactions. www.nature.com/scientificreports/ Fibrosis could be activated by external (e.g., RT) or endogenous (growth factors/cytokines) stimuli 37 . The common feature of the majority of fibrotic tissues is the overexpression of TGF-β, the most potent profibrotic cytokine 27 .…”

Cancer-Associated Fibroblasts Differentiated by Exosomes Isolated from Cancer Cells Promote Cancer Cell Invasion

“…For example, with regard to the omental tumor microenvironment, omental fibroblasts are trans-differentiated from adipose-derived mesenchymal stem cells by ovarian cancer-derived exosomes and are associated with transforming growth factor beta (TGF-β) signaling secreted by both cancer cells and stromal cells [19,20]. TGF-β contributes to recruiting stromal cell types characterized by CAFs, inducing ECM production and downregulating the expression of ECM-associated protease [21].…”

Impact of FAPI-PET/CT on Target Volume Definition in Radiation Therapy of Locally Recurrent Pancreatic Cancer

“…Recent studies however have also suggested that CAFs provide the tumors with a pro-cancerous microenvironment and can serve as the leading structures for cancer progression [27,28]. These lowuptake lesions surrounding the tumor might therefore be precancerous, so far overlooked by radiation oncologists, thus requiring targeted radiation [29]. This hypothesis first requires validation through the gold standard of histopathological correlation in future studies.…”