Anti-L-selectin monoclonal antibody treatment in mice enhances tumor growth by preventing CTL sensitization in peripheral lymph nodes draining the tumor area.
To examine the in vivo contribution of L-selectin in the sensitization of tumor-specific CTL, we investigated the effects of treatment with the anti-L-selectin monoclonal antibody (MAb) MEL-14 on the immune response to Moloney-murine sarcoma virus (M-MSV)-induced tumors, which exhibit spontaneous regression following generation of a strong virus-specific CTL response. Daily systemic administration of MEL-14 for 10 days to M-MSV-injected mice gave rise to larger sarcomas that persisted for a longer time, compared with those arising in control mice injected with virus only. The enhanced tumor growth could not be attributed to cytotoxic activity on leukocytes by MEL-14 since no reduction in the total cell number was detected in peripheral blood and spleen of MAb-treated mice. Evaluation of the immunological response in MAb-treated animals revealed a strong reduction in the generation of virus-specific CTL precursors (CTLp) in tumor-draining peripheral lymph nodes (PLN) 10 and 15 days after M-MSV injection, while in spleen, where lymphocyte localization is independent of L-selectin expression, CTLp generation was only delayed. By day 20, when tumors had begun to regress, the CTLp number showed a marked increase in both spleen and local PLN, where naive recirculating CTL could now enter because L-selectin was no longer down-regulated or blocked by the injected MAb. Our findings indicate that functional inactivation of L-selectin by MEL-14 treatment prevented migration of naive L-selectin+CTL through high endothelial venules (HEV) and their accumulation in PLN draining the tumor area, thereby precluding the initiation of a tumor-specific CTL response that takes place primarily at this site.
Rosato
A
A
Institute of Oncology, Inter-University Center for Cancer Research, University of Padua, Italy.
Zambon
A
A
Macino
B
B
Mandruzzato
S
S
Bronte
V
V
Milan
G
G
Zanovello
P
P
Collavo
D
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002472:Cell Transformation, Viral; D019041:L-Selectin / Q000276:immunology*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008980:Moloney murine sarcoma virus; D051381:Rats; D012192:Retroviridae Infections / Q000821:virology; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014412:Tumor Virus Infections / Q000821:virology
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D019041:L-Selectin