Data from 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.