Activated NKT Cells and NK Cells Render T Cells Resistant to Myeloid-Derived Suppressor Cells and Result in an Effective Adoptive Cellular Therapy against Breast Cancer in the FVBN202 Transgenic Mouse

作者：Kmieciak Maciej; Basu Debasmita; Payne Kyle K; Toor Amir; Yacoub Adly; Wang Xiang Yang; Smith Lisa; Bear Harry D; Manjili Masoud H^*

来源：The Journal of Immunology, 2011, 187(2): 708-717.

DOI：10.4049/jimmunol.1100502

Attempts to cure breast cancer by adoptive cellular therapy (ACT) have not been successful. This is primarily due to the presence of tumor-induced immune-suppressive mechanisms as well as the failure of tumor-reactive T cells to provide long-term memory responses in vivo. To address these clinically important challenges, we developed an ex vivo protocol for the expansion of tumor-reactive immune cells obtained from tumor-bearing animals prior to or after local radiation therapy. We used an Ag-free protocol that included bryostatin 1/ionomycin and sequential common gamma-chain cytokines (IL-7/IL-15 + IL-2). The proposed protocol expanded tumor-reactive T cells as well as activated non-T cells, including NKT cells, NK cells, and IFN-gamma-producing killer dendritic cells. Antitumor efficacy of T cells depended on the presence of non-T cells. The effector non-T cells also rendered T cells resistant to myeloid-derived suppressor cells. Radiation therapy altered phenotypic distribution and differentiation of T cells as well as their ability to generate central memory T cells. ACT by means of the expanded cells protected animals from tumor challenge and generated long-term memory responses against the tumor, provided that leukocytes were derived from tumor-bearing animals prior to radiation therapy. The ex vivo protocol was also able to expand HER-2/neu-specific T cells derived from the PBMC of a single patient with breast carcinoma. These data suggest that the proposed ACT protocol should be studied further in breast cancer patients. The Journal of Immunology, 2011, 187: 708-717.

• 出版日期2011-7-15