Background Checkpoint blockade is increasingly becoming a valuable immunotherapeutic tool in the management of advanced malignancies. Monoclonal antibodies (mAb) that target CTLA-4 have significantly extended survival of patients with metastatic melanoma, however the number of responders remain low. We have previously shown in the 4T1 mouse tumor model that resistance to anti-CTLA-4 therapy can be overcome by concurrent local radiotherapy (RT) (Demaria et al 2005 Clin Can Res 11:728). Improved response was, in part, the result of radiation’s ability to promote priming, and enhance homing of effector cytotoxic T cells to the tumor and their interactions with tumor cells (Matsumura et al 2008 J Immunol 181; Ruocco et al 2012 J Clin Invest 122:10). Here we used high throughput sequencing of T cell receptor (TCR) b chain to interrogate the breadth and depth of tumor infiltrating lymphocytes (TILs) repertoire changes in 4T1 tumors after treatment with anti-CTLA-4 therapy given in conjunction with radiotherapy.