Enhancing the Effectiveness of Breast Cancer Immunotherapy Through Manipulation of the T Cell Cytoskeleton
Abstract
A limitation of specific adoptive immunotherapy this therapy is the poor survival and tumor localization of activated T cells after infusion into a host. A contributor to these problems is the appendage-bearing, adhesive form of activated T cells, which renders them poorly suited to circulate, and likely to embolize in microvasculature. We hypothesized that transient inhibition of T cell appendage formation and adhesiveness, induced just before infusion, will improve the survival and circulation of adoptively transfered T cells. We found previously that pretreatment of activated T cells with the myosin light-chain kinase inhibitor ML-7 renders the cells temporarily smooth and nonadhesive. In this project we developed an ML-7 pretreatment protocol which allowed activated T cells to recover normal adhesion, motility, cytotoxicity, and proliferation within 24 hr. We then found that this protocol decreased by eightfold the percentage of infused cells trapped in the lung and increased fourfold the homing of ErbB2-specific T cells to the ErbB2+ murine mammary tumor D2F2/E2. Homing of infused T cells to peripheral lymph nodes was also increased by a factor of 1.5. When tested in. a D2F2/E2 immunotherapy model, the ML-7 pretreatment of T cells was found neither to enhance nor reduce the tumor-delaying effects of T cell infusion in D2F2/E2-bearing mice. The results constitute the first proof that cytoskeletal alteration of T cells can improve their trafficking behavior after adoptive transfer. On the basis of our initial test, though it appears that this strategy alone is enough to enhance adoptive immunotherapy. The ML-7 depolarization strategy is easily combined with other new methods of improved- immunotherapy, such as transduction of T cells with cytokines and survival genes, and such combinations should be tested in the future.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2004
- Accession Number
- ADA430569
Entities
People
- Stuart Ratner
Organizations
- Wayne State University