title: T cells and stromal fibroblasts in human tumor microenvironments represent potential therapeutic targets.
abstract: The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.
authors.affiliation: Department of Microbiology and Immunology, Witebsky Center, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 138 Farber Hall, 3435 Main Street, Buffalo, NY 14214 USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Barnas
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Simpson-Abelson
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Yokota
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kelleher
authors.forename: Richard B
authors.initials: RB
authors.lastname: Bankert