Enhancing the Effectiveness of Breast Cancer Immunotherapy through Manipulation of the T Cell Cytoskeleton
Annual rept. 15 Aug 2001-14 Aug 2002
WAYNE STATE UNIV DETROIT MI
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Adoptive immunotherapy, the in vitro activation and infusion of patient T cells, is a potentially useful immunotherapeutic strategy, but its effectiveness is limited by the poor trafficking and tumor localization of the infused cells. This is caused in part by the trapping and damage of many of the cells during their initial passages through pulmonary microvasculature. Trapping is promoted by the complex adhesive appendages which are characteristic of T cells activated in vitro. We now report that pulmonary trapping of activated T cells was reduced, and their tumor homing to s.c mammary tumors was increased, by rendering them temporarily smooth and nonadhesive. This was accomplished through treatment with ML-7, an reversible inhibitor of myosin function. ErbB2-specific T cells were labeled with fluorescent dye and tracked after infusion into mice bearing the ErbB2-expressing tumor D2F2E2. ML-7-treated cells showed an 8-fold reduction in 30-min pulmonary localization, relative to controls. Localization in s.c D2F2E2 tumors increased fourfold at 24 and 48 hr. T cell- mediated anti-D2F2 cytotoxicity in vitro was transiently depressed by ML-7 treatment but recovered fully within 24 hr. The results provide the first validation of the concept that appropriate cytoskeletal alterations can improve T cell localization in tumors after adoptive transfer.
- Medicine and Medical Research