Targeting TNF-α to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy.
Abnormal tumor vasculature impairs T lymphocyte adhesion to endothelial cells and lymphocyte extravasation into neoplastic tissues, limiting the therapeutic potential of both active and adoptive immunotherapies. We have found that treatment of tumor-bearing mice with NGR-TNF, a Cys-Asn-Gly-Arg-Cys peptide-TNF fusion product capable of altering the endothelial barrier function and improving drug penetration in tumors, associated with the intratumor upregulation of leukocyte-endothelial cell adhesion molecules, the release of proinflammatory cytokines and chemokines, and the infiltration of tumor-specific effector CD8(+) T cells. As a result, NGR-TNF enhanced the therapeutic activity of adoptive and active immunotherapy, delaying tumor growth and prolonging survival. Furthermore, we have found that therapeutic effects of these combinations can be further increased by the addition of chemotherapy. Thus, these findings might be relevant for the design of novel immunotherapeutic approaches for cancer patients.
Cellular Immunology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy. corti.angelo@hsr.it
Arianna
A
Calcinotto
Matteo
M
Grioni
Elena
E
Jachetti
Flavio
F
Curnis
Anna
A
Mondino
Giorgio
G
Parmiani
Angelo
A
Corti
Matteo
M
Bellone
D000818:Animals; D002469:Cell Separation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology* / Q000628:therapy; D009389:Neovascularization, Pathologic; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha