Depletion of CD4+ cells in tumor-bearing mice has strong anti-tumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4+ cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the anti-tumor effects of an anti-CD4 depleting monoclonal antibody (mAb) as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26 or LLC subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong anti-tumor effects that were superior to those elicited by CD25+ Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8+ cell depletion. CD4+ cell depletion led to the proliferation of tumor-specific CD8+ T cells in the draining lymph node and increased infiltration of PD-1+CD8+ T cells into the tumor, with a shift towards type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti-CD4 and anti-PD-1 or anti-PD-L1 mAb therapies.
- Received October 8, 2014.
- Revision received February 1, 2015.
- Accepted February 15, 2015.
- Copyright © 2015, American Association for Cancer Research.