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

BACKGROUND

Yttrium-90 transarterial radioembolization (90Y) 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 are unknown.

DESIGN

Paired blood specimen were collected prior to first-cycle 90Y and at imaging follow-up in patients with HCC stage BCLC-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 mRECIST and defined as either OR or non-objective (NOR). Time-to-progression(TTP) was defined as progression to BCLC-C within 6-months following 90Y.

RESULTS

90Y induced shifts in both CD4+ (P=0.049) and CD8+ (P<0.001) toward an effector memory (TEM) response independent of treatment response rate. Non-responders to 90Y were characterized by a sustained elevation in both naïve CD4+ cells (P=0.019) and PD-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, HR10.8) and 75% disease progression rates 6-months following treatment.

CONCLUSION

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 NOR.