Reciprocal Functional Modulation of the Activation of T Lymphocytes and Fibroblasts Derived from Human Solid Tumors

Abstract

Fibroblasts are a dominant cell type in most human solid tumors. The possibility that fibroblasts have the capacity to interact with and modulate the function of tumor-associated T lymphocytes makes them a potential therapeutic target. To address this question, primary cultures of fibroblasts derived from human lung tumors were established and cultured with T cells derived from the same tumor. The tumor fibroblasts significantly enhance the production of IFN-γ and IL-17A by the tumor-associated T cells following a CD3/CD28-induced activation of the T cells. This enhancement was fibroblast cell dose-dependent and did not require direct contact between the two cell types. Tumor-associated fibroblast-conditioned media similarly enhanced both IFN-γ and IL-17A in activated T cells, and this enhancement was significantly reduced by Abs to IL-6. Conditioned media derived from activated lymphocyte cultures significantly enhanced IL-6 production by tumor fibroblasts. A similar enhancement of IFN-γ and IL-17A was observed when activated T cells from a normal donor were cultivated with skin fibroblasts derived from the same donor. These results establish that fibroblasts and autologous lymphocytes, whether derived from the tumor microenvironment or from nonmalignant tissues, have the capacity to reciprocally interact and modulate function. In contrast to other reports, fibroblasts are shown to have an immunostimulatory effect upon activated T lymphocytes. The ability of fibroblasts to enhance two T cell cytokines known to have an impact upon tumor progression suggests that fibroblasts play an important role in tumor pathogenesis that could be exploited therapeutically.

A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells

“…Moreover, it was recently shown that T lymphocytes, on TCR activation, produce soluble factors that enhance fibroblasts production of IL-6. 22 An attractive hypothesis is that activated T cells release cytokines that might sustain the induction of the suppressive cells or maintain their tolerogenic activity, an autoregulative loop that has already been shown in a different system. 10 Among different cytokine combinations, GM-CSF and IL-6 were the most effective in generating, from healthy donor PBMCs, suppressive CD33 ϩ cells that inhibited the proliferation and IFN-␥ production by autologous human T cells after CD3/CD28 stimulation.…”

Human-derived normal mesenchymal stem/stromal cells in anticancer therapies

“…These data suggest that the tumor-promoting effect of MSCs is due to suppression of immune effector cells. TAFs could also induce CD3/CD28-dependent activation of T cells and do not appear to inhibit these effector cells 58.…”

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

“…Indeed, MSC downregulate effector lymphocyte activation using indoleamine 2,3 dioxygenase (IDO), heme oxygenase (HO), arginase 1 and 2 (ARG 1-2 ), nitric oxidase synthase 2 (NOS 2 ), hepatocyte growth factor (HGF), TGF-β, IL10, and prostaglandin E2 (PGE 2 ) [43,44,45,46,47,48]. Some of these inhibitory molecular mechanisms, such as IDO, PGE 2 , TGF-β, and IL-10, are shared with myeloid-derived suppressor cells, tumor cells, and infiltrating Treg lymphocytes present in TME [49,50].…”