Immune checkpoint blockade results in T cell antitumor responses but most patients fail to respond. This raises fundamental questions about mechanisms of tumor immune recognition and resistance. Here, I first report tumor regressions in a subset of patients with metastatic melanoma treated with anti-CTLA4 antibody and radiation (RT) and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common due to upregulation of PD-L1 on tumor cells and corresponding T cell exhaustion. Accordingly, optimal response in melanoma and other cancer types required RT, anti-CTLA4, and anti-PD-L1/PD1. When I investigated determinants of improved responses to combination therapy, I found that RT enhanced the antigenic diversity of intratumoral T cells, anti-CTLA4 predominantly inhibited regulatory T cells, and anti-PD-L1 reversed T cell exhaustion. I next extended my investigation of this combination therapy to pancreatic ductal adenocarcinoma (PDA), finding that optimal responses required addition of agonist CD40 monoclonal antibody.