Cirrhosis-Drive Immune Dysfunction Associates With Poor Response To Deb-Tace And Waitlist Dropout In Hepatocellular Carcinoma Patients

Abstract

Presenter: Kelley Nunez PhD | Ochsner Health System Background: Hepatocellular carcinoma (HCC) recurrence after transplantation is associated with higher tumor grade on explant, failure to respond to DEB-TACE, and pretreatment lymphopenia. We prospectively monitored HCC patients in transplant evaluation to investigate associations between lymphopenia and tolerance with treatment response and waitlist outcomes. Methods: HCC patients undergoing DEB-TACE were prospectively enrolled. Blood was collected before and after DEB-TACE (100-300μm LC Beads with 100mg doxorubicin). Peripheral blood mononuclear cells were analyzed by flow cytometry. Tumor response to DEB-TACE was determined using mRECIST imaging criteria. Intention-to-treat (ITT) endpoint included transplantation or tumor progression. Results: Analyzed were 91 patients with a median age 61, predominantly Caucasian (73%) with Hepatitis C (80%). Prior to DEB-TACE, 47% of patients were lymphopenic (absolute lymphocyte count, ALC≤1.2k/μL). Tumor response was scored using mRECIST and available in 82 patients. Pre-treatment ALC and lymphopenia status were associated with failure to respond to DEB-TACE (P=0.028, P=0.004). Overall, 69% of patients that did not respond to treatment were lymphopenic. These patients also exhibited significantly lower albumin (P=0.0017) and higher bilirubin (P=0.02) at the time of treatment. Interestingly, no significant changes were observed in lymphocyte count, albumin, and bilirubin levels between 3 years prior to HCC development, at the time of diagnosis, and day of treatment. Tolerogenic immune populations, myeloid derived suppressor cells (MDSC) and regulatory T cells were significantly elevated in lymphopenic patients (P=0.02 and P=0.001). MDSCs isolated from HCC patients exhibited immune suppressive activity. To investigate whether bilirubin could impact T cells, isolated human T cells were incubated with unconjugated bilirubin; Results showed no effect on proliferation. Sixty patients (66%) reached ITT endpoint with 30/60 transplanted and 30/60 waitlist dropout due to tumor progression. In the ITT cohort, 61% of patients that did not respond to treatment experienced tumor progression. Conclusion: Lymphopenic status remains stable prior to HCC development and may be cirrhosis-driven. Patients presenting with lymphopenia and poor liver synthetic function can identify patients with immune dysfunction both at risk of tumor progression prior to transplantation.