Enhancing antitumor immunity: combining IL-12 with TGFbeta1 antagonism.
With respect to CD8 effector T cells, interleukin-12 (IL-12) and transforming growth factor beta (TGFbeta) are 2 cytokines that exert opposing effects. IL-12 promotes antitumor immune responses by augmenting activated CD8 T-cell proliferation and interferon-gamma secretion. Conversely, TGFbeta generates a permissive environment for cancer growth, in part by antagonizing the effects of immunomodulatory cytokines, including IL-12. We demonstrate that TGFbeta-resistant T cells are capable of sustaining IL-12-induced mitogenesis and interferon-gamma secretion in a TGFbeta-rich milieu. Furthermore, in 2 murine tumor models associated with high TGFbeta1 levels in the local microenvironment, treatment with IL-12 and adoptively transferred TGFbeta-resistant T cells provided improved survival times. These results suggest that combining IL-12 with TGFbeta neutralization strategies may be effective in enhancing antitumor immune responses.
Fan
Timothy M
TM
Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, 1008 West Hazelwood Drive, Urbana, IL 61801, USA. tfan@cvm.uiuc.edu
Kranz
David M
DM
Roy
Edward J
EJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D008546:Melanoma, Experimental / Q000401:mortality / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D020288:Papilloma, Choroid Plexus / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D018664:Interleukin-12; D007371:Interferon-gamma