TNFRSF4 and neoplasm: There is evidence from human clinical trials that CTLA-4 blockade leads to peripheral Treg destabilization as a high frequency of patients experience gut toxicity and other autoimmune side effects.25 Little gut toxicity has been observed with the PD-1 blockade trials and this activity was not observed in patients treated with an OX40 agonist.19 Hence, although CTLA-4 blockade may have a role in peripheral tolerance potentially through Treg destabilization, all three immune-stimulatory strategies may have a role to destabilize Treg function or deplete Tregs within the tumor.