Gastric cancer cells exploit CD4+ cell-derived CCL5 for their growth and prevention of CD8+ cell-involved tumor elimination.
The level of serum CCL5, a C-C chemokine, is reportedly correlated with tumor progression in several cancers. We herein investigated the mechanisms by which CCL5 might contribute to tumor progression in gastric cancer. Serum CCL5 levels significantly correlated with tumor progression and prognosis in patients with gastric cancer. Immunohistochemistry showed that tumor-infiltrating lymphocytes expressed CCL5, while the tumor cells expressed the CCL5 receptors. Fluorescent double staining showed that tumor-infiltrating CD4+ cells rather than CD8+ cells preferentially expressed CCL5. Using gastric cancer cell lines (MKN45, KATO III), we examined CCL5 production by coculturing whole peripheral blood mononuclear cells (PBMCs), CD4+ cells, or CD8+ cells, with tumor cells. CD4+ cells cocultured with tumor cells remarkably enhanced CCL5 production in a direct cell-cell contact manner over other cocultured PBMCs, including CD8+ cells. Gastric cancer cell lines expressed CCL5 receptors and augmented their proliferation in response to CCL5 stimulation. Furthermore, we examined the effect of CCL5-treated cancer cells on the cocultured PBMCs, focusing on the CD4+/CD8+ proportion and apoptosis. Coculture of CCL5-treated gastric cancer cells with PBMCs resulted in a significant decrease in the proportion of CD8+ cells but not CD4+ cells, suggesting Fas-FasL-mediated apoptosis in CD8+ cells. In immunodeficient mice coinjected with KATO III and PBMCs, neutralization of CCL5 significantly suppressed tumor progression, resulting in a favorable outcome. In conclusion, gastric cancer cells might thus induce CD4+ T cells to secrete CCL5 and exploit it for their progression, as well as to aid in the prevention of CD8+ T cell-involved tumor elimination.
Sugasawa
Hidekazu
H
Department of Surgery, National Defense Medical College, Tokorozawa, Japan. grd1807@ndmc.ac.jp
Ichikura
Takashi
T
Kinoshita
Manabu
M
Ono
Satoshi
S
Majima
Takashi
T
Tsujimoto
Hironori
H
Chochi
Kentaro
K
Hiroi
Sadayuki
S
Takayama
Eiji
E
Saitoh
Daizoh
D
Seki
Shuhji
S
Mochizuki
Hidetaka
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000097:blood*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018946:Chemokine CCL5 / Q000097:blood* / Q000378:metabolism; D018920:Coculture Techniques; D018450:Disease Progression; D053222:Fas Ligand Protein / Q000276:immunology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D013274:Stomach Neoplasms / Q000097:blood* / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D016019:Survival Analysis; D019014:fas Receptor / Q000276:immunology
D014408:Biomarkers, Tumor; D018946:Chemokine CCL5; D053222:Fas Ligand Protein; D019014:fas Receptor