Yttrium-90 Induces an Effector Memory Response with Neoantigen Clonotype Expansion: Implications for Immunotherapy

Abstract Yttrium-90 (90Y) transarterial radioembolization can safely and effectively treat hepatocellular carcinoma (HCC). Clinical trials combining 90Y with immunotherapy are aimed at improving treatment response rates. The impact of transient 90Y-induced lymphopenia on T-cell homeostasis and functional dynamics is unknown. Paired blood specimens were collected prior to first-cycle 90Y and at imaging follow-up in patients with HCC Barcelona Clinic Liver Cancer stages A–B. Flow cytometry and T-cell receptor (TCR) sequencing were used to monitor changes in T-cell subsets and TCR repertoire following 90Y. Objective response (OR) rates were determined using modified RECIST and defined as either OR or nonobjective response. Time-to-progression (TTP) was defined as progression to Barcelona Clinic Liver Cancer stage C within 6 months following 90Y. 90Y induced shifts in both CD4+ (P = 0.049) and CD8+ (P 0.001) toward an effector memory T-cell response independent of treatment response rate. Nonresponders to 90Y were characterized by a sustained elevation in both naïve CD4+ cells (P = 0.019) and programmed cell death protein 1 expression in CD8+ cells (P = 0.003). Paired analysis of the TCR repertoire revealed a variable induction of neoantigen clonotypes and expansion of existing clonotypes independent of 90Y response. In patients with an OR, changes in TCR clonality did not influence TTP. However, polyclonal profiles in patients without an OR were associated with shorter TTP (P = 0.005; HR, 10.8) and 75% disease progression rates 6 months following treatment. 90Y induces a population shift from central to effector memory accompanied by neoantigen T-cell responses independent of treatment response rate. Monoclonal shifts in the post-90Y T-cell repertoire had superior overall TTP and improved TTP in patients with a first-cycle nonobjective response. Significance: 90Y can safely treat HCC; however, it causes transient lymphopenia. In this article, 90Y stimulates a peripheral effector memory response independent of initial treatment response. TCR sequencing revealed that polyclonal profiles in patients without an OR to treatment were associated with rapid progression rates 6 months after 90Y.