Enhancement of T cell localization in mammary tumors through transient inhibition of T cell myosin function.
Adoptive immunotherapy is hampered by poor lymphocyte localization in tumors. The polarized, adhesive phenotype of activated lymphocytes may contribute to this problem by making the cells prone to trapping and damage in pulmonary microvasculature. We found that transient inhibition of T cell polarization prior to i.v. infusion reduces trapping and improves tumor localization. Activated T cells were rendered nonpolar and nonadhesive by treatment with myosin light-chain kinase inhibitor ML-7. Polarity, adhesiveness, and motility recovered by 6 h after treatment, cytotoxicity, and proliferation by 24 h. ErbB2-specific T cells were infused i.v. into mice bearing ErbB2-expressing mammary tumors. ML-7 pre-treatment reduced T cell arrest in lungs by a factor of eight, improved tumor localization by 4-fold, and increased lymph node homing. Although this improvement alone proved insufficient to alter outcome in an immunotherapy experiment, this study indicates that cytoskeletal modification is a promising strategy for altering the trafficking of infused lymphocytes.
Ratner
Stuart
S
Breast Cancer Research Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA. ratners@kci.wayne.edu
Wei
Wei-Zen
WZ
Oliver
Jeffrey
J
Oliver
Jennifer
J
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007262:Infusions, Intravenous; D008168:Lung / Q000166:cytology / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009218:Myosins / Q000187:drug effects* / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D001381:Azepines; D009219:Myosin-Light-Chain Kinase; D009218:Myosins; D009281:Naphthalenes; D018719:Erb-b2 Receptor Tyrosine Kinases; C070571:ML 7