Co-evolution of fibroblasts and immune cells in inflammation and cancer

Fibroblasts are fundamental for tissue homeostasis. Their main function under normal conditions is maintaining tissue integrity.  Fibroblasts orchestrate tissue repair, mediated by ECM synthesis and remodeling, and regulation of immune cell responses. In the tumor microenvironment, the regulatory ability of fibroblasts is hijacked by cancer cells making them cancer-associated fibroblasts (CAFs). CAFs manipulate the immune landscape in the TME, promoting cancer growth, immune escape, and metastatic dissemination. This is achieved through the secretion of cytokines and chemokines, the recruitment of suppressive myeloid and regulatory T cells, the suppression and exclusion of cytotoxic lymphocytes and dendritic cells, and the promotion of M2 and Th2 polarization of macrophages and T cells, respectively. Over the last decade, our understanding of CAFs has evolved with new technologies enabling new insights on the diverse roles of CAFs. Broadly 3 main subtypes were found across tumors -  myofibroblastic, immune-regulatory, and antigen-presenting. With the growing appreciation of CAF heterogeneity came the realization that their immune regulatory activity can change quite drastically depending on context. Some CAF subpopulations can promote inflammation while others promote immune suppression; some regulate macrophages, whereas others regulate T-cell activation - and although these functions were found across tumors, there is still much to discover regarding the mechanisms that influence these interactions and possible ways to target them. We aim to further dissect the evolution of fibroblasts and the structural microenvironment in inflammation and cancer, and to elucidate how fibroblasts regulate innate and adaptive immunity.