Host-derived MCP-1 and MIP-1α regulate protective anti-tumor immunity to localized and metastatic B16 melanoma.
Leukocytic infiltration into malignant melanoma lesions is tightly regulated by chemokines. To assess the role of the CC chemokines monocyte chemotactic protein-1 (MCP-1/chemokine ligand 2) and macrophage inflammatory protein-1α (MIP-1α/chemokine ligand 3) in this process, s.c. primary and metastatic B16 F10 melanoma tumor growth levels were examined in mice lacking MCP-1 or MIP-1α. Primary s.c. B16 F10 melanoma growth was augmented by loss of MCP-1 or MIP-1α. Similarly, lung metastasis was enhanced by the deficiency of MCP-1 or MIP-1α. Enhanced tumor outgrowth was associated with decreased percentages of infiltrating CD4(+) T cells, CD8(+) T cells, and natural killer cells. In the absence of MCP-1 or MIP-1α, melanoma outgrowth was correlated with reduced local expression of interferon-γ, IL-6, tumor necrosis factor-α, and transforming growth factor-β. Among these cytokines, reduced expression levels of interferon-γ and tumor necrosis factor-α on leukocytes from the spleen were associated with the development of lung metastasis in chemokine-deficient mice. The local s.c. administration of these four cytokines significantly augmented another chemokine's expression and suppressed primary melanoma growth in mice deficient for MCP-1 or MIP-1α. The s.c. injection of MCP-1 or MIP-1α significantly inhibited the primary tumor growth in wild-type mice. These results indicate that host-derived MCP-1 and MIP-1α regulate protective anti-tumor immunity to B16 F10 melanoma by promoting lymphocyte infiltration into the tumor and subsequent cytokine production.
Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
Yuko
Y
Nakasone
Manabu
M
Fujimoto
Takashi
T
Matsushita
Yasuhito
Y
Hamaguchi
Doanh Le
DL
Huu
Mizuki
M
Yanaba
Shinichi
S
Sato
Kazuhiko
K
Takehara
Minoru
M
Hasegawa
D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D018932:Chemokine CCL2 / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D054405:Chemokine CCL3 / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D007694:Killer Cells, Natural; D007962:Leukocytes / Q000502:physiology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology*; D015996:Survival Rate
D018932:Chemokine CCL2; D054405:Chemokine CCL3; D016207:Cytokines; D012333:RNA, Messenger