Depletion of regulatory T cells in tumors with an anti-CD25 immunotoxin induces CD8 T cell-mediated systemic antitumor immunity
Menée à l'aide de modèles murins de mésothéliome, de cancer du sein ou du côlon, cette étude met en évidence l'intérêt d'une immunotoxine ciblant l'antigène CD25 pour réduire la quantité de lymphocytes T régulateurs dans la tumeur et induire une immunité antitumorale systémique impliquant les lymphocytes T CD8+
Résumé en anglais
Regulatory T cells (Tregs) protect cancer cells from immune attack. Tregs express CD25 on their surface and can be killed by antibodies and immunoconjugates targeting CD25. These agents have not been effective in controlling tumor growth, probably because they also kill cytotoxic CD8 T cells expressing CD25 that are needed for antitumor activity. To overcome these deficiencies, we have directly injected tumors with a potent anti-CD25 immunotoxin, 2E4-PE38, that kills CD25-expressing Treg cells in the tumor, causes injected and distant tumors to regress, and induces antitumor immunity. Because 2E4-PE38 is present at very low concentrations in the blood, it does not kill CD25-expressing cells at distant sites. This strategy could be employed for treating tumors in people.The tumor microenvironment plays a critical role in controlling tumor progression and immune surveillance. We produced an immunotoxin (2E4-PE38) that kills mouse cells expressing CD25 by attaching the Fv portion of monoclonal antibody 2E4 (anti-mouse CD25) to a 38-kDa portion of Pseudomonas exotoxin A. We employed three mouse cancer tumor models (AB1 mesothelioma, 66c14 breast cancer, and CT26M colon cancer). Tumors were implanted at two sites on BALB/c mice. On days 5 and 9, one tumor was directly injected with 2E4-PE38, and the other was not treated; 2E4-PE38 produced complete regressions of 85% of injected AB1 tumors, 100% of 66c14 tumors, and 100% of CT26M tumors. It also produced complete regressions of 77% of uninjected AB1 tumors, 47% of 66c14 tumors, and 92% of CT26M tumors. Mice with complete regressions of 66c14 tumors were immune to rechallenge with 66c14 cells. Mice with complete regressions of AB1 or CT26M tumors developed cross-tumor immunity rejecting both tumor types. Injection of anti-CD25 antibody or a mutant inactive immunotoxin were generally ineffective. Tumors were analyzed 3 days after 2E4-PE38 injection. The number of regulatory T cells (Tregs) was significantly reduced in the injected tumor but not in the spleen. Injected tumors contained an increase in CD8 T cells expressing IFN-γ, the activation markers CD69 and CD25, and macrophages and conventional dendritic cells. Treatment with antibodies to CD8 abolished the antitumor effect. Selective depletion of Tregs in tumors facilitates the development of a CD8 T cell-dependent antitumor effect in three mouse models.
