Intratumoral expression of macrophage-derived chemokine induces CD4+ T cell-independent antitumor immunity in mice.
Macrophage-derived chemokine is chemotactic for a variety of leukocytes, and has been shown to be involved in T 2-mediated cellular immunity. To evaluate the role of this chemokine in tumor immunity in vivo, an adenovirus vector encoding the human macrophage-derived chemokine cDNA (AdMDC) was administered to established murine tumors. Gene transfer with AdMDC significantly inhibited tumor growth and prolonged animal survival. AdMDC was not directly cytotoxic to tumor cells, but splenocytes from animals that received intratumoral AdMDC were able to lyse syngeneic tumor cells, and purified splenic CD8 cells secreted interferon-gamma in a tumor-specific manner. The antitumor activity of AdMDC was lost in mice lacking CD8 T lymphocytes, but surprisingly, it was preserved in animals lacking CD4 cells, as was the systemic cytotoxic T lymphocyte response. Systemic NK cells did not play a role in the antitumor immune response induced by AdMDC. Experiments using knockout mice demonstrated that host expression of MHC Class I, but not Class II, IL-4, or IL-12, was necessary for AdMDC to exert its antitumor effect, and immunohistochemistry demonstrated infiltrates of CD8 and CD86 cells, but not CD4 cells in treated tumors. These studies highlight a new function for macrophage-derived chemokine by demonstrating that it possesses in vivo antitumor activity with CD8 T cells as the effector cells, and interestingly, that the CD4 cell/MHC II pathway of CD8 cell activation is not required for the antitumor effects of this chemokine.(H)
Lee
Jay M
JM
Deparment of Cardiothoracic Surgery, Division of Pulmonary and Critical Care Medicine, Sloan-Kettering Cancer Center, New York, NY, USA.
Merritt
Robert E
RE
Mahtabifard
Ali
A
Yamada
Reiko
R
Kikuchi
Toshiaki
T
Crystal
Ronald G
RG
Korst
Robert J
RJ
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000235:genetics* / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000628:therapy; D011336:Probability; D051381:Rats; D018709:Statistics, Nonparametric; D015996:Survival Rate; D014162:Transfection; D016896:Treatment Outcome
C515482:CCL22 protein, human; C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D019742:Chemokines, CC