The present invention relates to combination therapies comprising at least one activator of Tie-2 and immunotherapies that target immune checkpoints. Combination therapies of the disclosure can provide therapeutic effects not obtained with singly-administered immunotherapies. Combination therapies can be used to increase the therapeutic efficacy of an immunotherapy, to provide lower dosages of an immunotherapy being administered, to lower a toxicity of an immunotherapy, or to manage a side effect of an immunotherapy.