Chimeric NKG2D expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment.

The Journal of Immunology : Official Journal of the American Association of Immunologists
Amorette BarberCharles L Sentman

Abstract

Adoptive transfer of T cells expressing chimeric NKG2D (chNKG2D) receptors, a fusion of NKG2D and CD3zeta, can lead to long-term, tumor-free survival in a murine model of ovarian cancer. To determine the mechanisms of chNKG2D T cell antitumor efficacy, we analyzed how chNKG2D T cells altered the tumor microenvironment, including the tumor-infiltrating leukocyte populations. chNKG2D T cell treatment of mice bearing ID8 tumor cells increased the number and activation of NK cells and increased the activation of host CD8+ T cells within the tumor. Foxp3+ regulatory T cells at the tumor site decreased more than 300-fold after chNKG2D T cell treatment. Tumor-associated regulatory T cells expressed cell surface NKG2D ligands and were killed by chNKG2D T cells in a perforin-dependent manner. chNKG2D T cells also altered the function of myeloid cells at the tumor site, changing these cells from being immunosuppressive to enhancing T cell responses. Cells isolated from the tumor produced elevated amounts of IFN-gamma, NO, and other proinflammatory cytokines after chNKG2D T cell treatment. ChNKG2D T cells required perforin, IFN-gamma, and GM-CSF to induce a full response at the tumor site. In addition, transfer of chNKG2D T cells into mic...Continue Reading

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