Tracing anti-cancer immunity in patients undergoing liver transplantation for HCC after downstaging with immunotherapy

Introduction Hepatocellular carcinoma (HCC) patients treated with combinatorial immunotherapy (CIT) including anti-angiogenics and immune checkpoint inhibitors (atezolizumab and bevacizumab) can achieve tumor downstaging and become eligible to liver transplantation (LT). While CIT may increase the risk of graft rejection, LT-associated immunosuppression may exert detrimental effects on anti-tumor immunity. Aim Patients with intermediate-advanced HCC downstaged to accepted LT criteria, underwent circulating anti-tumor cell immunomonitoring. Here we show the behaviour of memory and effector T cell subsets during treatment, during the washout phase, at early and late post-LT follow-up, with the aim of uncovering immune responses that regulate tumor immunosurveillance. Material and Methods Four HCC patients undergoing LT after CIT downstaging (median 120 days on treatment) followed by a 2 month (median 70.5 days) wash-out phase underwent peripheral blood sampling at different time points (end of treatment, during the wash-out phase and up to 5 months after LT). High resolution flow cytometry was performed on whole blood to quantify cells expressing lymphoid markers, with particular regards to CD8+ memory and effector T cell subsets. Results Flow cytometry data show that CIT induced a boost of naïve, effector memory (TEM) and terminally differentiated effector memory (TEMRA) T cells that decreases rapidly within the first 30 days of the wash-out phase with a further reduction at early post-LT time points (3-7 days) because of the enhanced immunosuppressive regimen. Nevertheless, within the first month and even more at a five-month post-LT follow-up, most of the effector and memory T cell subsets encompassing anti-tumor responses, regain levels even higher than on-treatment values. Conclusions The post-liver transplant regaining of anti-tumor immune cell levels, despite immunosuppression, at levels higher than on-CIT treatment, justifies further investigation in the field and suggests a possible role of organ transplantation as an endogenous adjuvant to aid in adaptive immune responses.