To gain mechanistic insights for designing more effective combination immunotherapies, we utilized the challenging B16 murine melanoma model to investigate the nature of the intratumoral immune response induced by checkpoint blockade with anti-PD-1 or anti-CTLA-4 monoclonal antibodies (mAbs), or immunostimulatory anti-4-1BB antibody6 or anti-CD4 mAb which can deplete immunosuppressive leukocyte populations7. Here, CTLA4 is linked to melanoma.