Fibroblast modulation of T lymphocyte activation
Barnas, Jennifer Lynn
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Fibroblasts are a dominant cell type amongst the mixed population of tumor, stromal, and inflammatory cells found in the microenvironment of 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 how fibroblasts modulate the response of T lymphocytes to activation, primary cultures of fibroblasts derived from human non-small cell lung tumors were established and cultured with T cells derived from the same tumor. The tumor-associated fibroblasts significantly enhance the production of interferon-γ (IFN-γ) and interleukin-17A (IL-17A) by the tumor-associated T cells following a CD3/CD28-induced activation of the T cells. This enhancement is fibroblast cell dose-dependent and does not require direct contact between the two cell types. Tumor-associated fibroblast-conditioned media similarly enhances both IFN-γ and IL-17A in activated T cells, and this enhancement is significantly reduced by neutralizing antibodies to interleukin-6 (IL-6). Conditioned media derived from activated lymphocytes significantly enhances IL-6 production by tumor fibroblasts and this is mediated through tumor necrosis factor-α (TNF-α) and IL-17A present in the lymphocyte conditioned media. A similar enhancement of IFN-γ and IL-17A is observed when activated peripheral blood T cells from a normal donor were cultivated with skin fibroblasts derived from the same donor. These results establish that fibroblasts and T lymphocytes, whether derived from the tumor microenvironment or from non-malignant tissues, reciprocally interact and modulate each other's function. In contrast to other reports, fibroblasts are shown here to have a net immunostimulatory effect upon activated T lymphocytes. While the ability of fibroblasts to alter the levels of two T lymphocyte-produced cytokines known to play a role in tumor pathogenesis makes the tumor-associated fibroblasts an attractive target for therapeutic manipulation, conflicting reports within the literature on how fibroblasts modulate immune function suggest that a deeper understanding of the dynamics between fibroblasts and T lymphocytes is still needed.