The recent development of immune-checkpoint Abs has revolutionized our concept of cancer therapy. We have clinically developed a humanized anti-CCR4 Ab with potent ADCC activity against Adult T-cell leukemia lymphoma (ATLL). Due to selective expression of CCR4 on Tregs, this Ab is also also expected to overcome cancer-associated immune-suppression through the depletion of Tregs. We are also developing a humanized anti-CD4 Ab with potent ADCC activity, IT1208. In murine subcutaneous tumor models (B16 melanoma, Colon 26, and LLC), administration of the anti-CD4 Ab alone had strong antitumor effects that were superior to those elicited by CD 25+ Treg depletion or by any immune checkpoint Abs. CD4+ T cell depletion led to the activation and enhanced migration of tumor-associated DCs into the D-LN, consequent oligoclonal expansion of tumor-specific CD8+T cells in the D-LN, 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 Ab and anti-PD-1/PD-L1 Ab synergistically suppressed tumor growth and greatly prolonged survival. A first-in-human Phase I clinical trial targeting solid tumors is going on in National Cancer Research Center, Japan. We also expect to develop a CCR2-associated FROUNT antagonist to block MDSC infiltration, and an Alarmin HMGN-1 to activate DCs for further improvement of cancer immunotherapy using anti-CD4 and PD-1 Abs.