We hypothesized that similar changes in MDSC and Treg may be observed with ipilimumab in the neoadjuvant/adjuvant setting that may be best evaluated in a (+)-JQ1 neoadjuvant study that provides parallel evaluation in the circulation and the tumor microenvironment of suppressor and effector immune cells. We have therefore conducted a neoadjuvant translational evaluation of ipilimumab at 10 mg/kg in patients with locally and/or regionally advanced melanoma, with the primary goal of generating biomarker data and providing a preliminary assessment of efficacy and safety of neoadjuvant ipilimumab as secondary endpoints. Primarily, we pursued the monitoring of cellular markers of immunosuppression and of effector T cells before and after ipilimumab as assessed in the TME and in the circulation, testing the hypothesis that these biomarkers will be significantly modulated and may have therapeutic predictive roles. Such findings may be further tested in larger adjuvant trials involving ipilimumab. The neoadjuvant application of ipilimumab in this trial has allowed the monitoring of the immunomodulatory effects of ipilimumab in the circulation and the tumor microenvironment of patients treated and the testing of mechanistic hypotheses. Clinically, the evaluation of efficacy was meant to be descriptive given the small sample size and the lack of a control group. The study enrolled patients with melanoma recurrence and mortality risk that is the highest among those considered potentially operable, including 27 patients with recurrent disease. In addition, 18 patients had a component of in-transit metastatic disease. The PFS and OS rates observed may therefore be considered favorable, with the noted caveats of the statistical limitations of small single arm studies. The most common adverse events related to ipilimumab were immune mediated, were consistent with the known toxicity profile of this agent at 10 mg/kg and were manageable utilizing established toxicity management guidelines. The outcomes of the peripheral monitoring of Treg and MDSC as mediators of immune suppression were consistent with our prior observations in patients with metastatic melanoma treated with the combination of tremelimumab and HDI. This raises questions about the functional status of these Treg that should be further pursued, although the opposite change in Treg was observed in the TME and the clinical activity does not appear to have been negatively affected by the circulating Treg increase. These findings are consistent with our report of a similar impact of tremelimumab/HDI on circulating Treg in metastatic melanoma in the presence of significant clinical activity, but no post treatment tumor samples were available to assess Treg in the TME in that study. Moreover, it is interesting to note that Me´nard et al. had demonstrated that CTLA-4 blockade with tremelimumab in advanced melanoma patients restored the circulating effector and memory CD4+ and CD8+ T cell pool and TCR-dependent T-cell proliferation that became resistant to Treg-mediated suppression.