Pre-treatment ZNF683⁺ effector CD8⁺ T cells predict response to BiTE therapy in acute lymphoblastic leukemia: Insights from single-cell and TCR sequencing
Year: 2025
Type: conference-abstract
Abstract: Introduction: Bispecific T cell engager (BiTE) therapy has shown meaningful activity in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), but primary resistance limits its broader efficacy. Emerging evidence suggests that the pre-existing state and clonal composition of T cells shape responsiveness to T cell–directed immunotherapies. ZNF683, a transcription factor enriched in tissue-resident and terminally differentiated cytotoxic CD8⁺ T cells, has been implicated in sustained antitumor immunity in solid tumors, yet its relevance to BiTE response in B-ALL is unexplored. Methods: We conducted paired single-cell RNA and TCR sequencing on 16 peripheral blood samples from 8 patients with B-ALL treated with BiTE therapy. Samples were collected at baseline and at 1–2 weeks post-treatment. Patients were classified as responders (n=4) or non-responders (n=4) based on clinical outcomes. Flow cytometry was used to validate key activation phenotypes. Results: Post-treatment, responders exhibited increased proportions of CD14⁺ monocytes and exhausted CD8⁺ T cells, whereas non-responders showed a marked expansion of regulatory T cells (Treg). At baseline, responders harbored dominant TCR clones within effector CD8⁺ T cells expressing high levels of ZNF683 alongside cytotoxic molecules GZMH, NKG7, GNLY, and CD52. ZNF683 expression was inversely correlated with memory and early activation markers (CD27, TCF7, CD69, JUND), consistent with terminal effector differentiation. Cell–cell communication analysis further revealed that effector CD8⁺ T cells in responders engaged in significantly stronger inferred interactions with B cells compared to non-responders, suggesting a supportive cross-talk network that may potentiate anti-leukemic activity. In contrast, non-responders lacked expanded cytotoxic clones and instead displayed a CD8⁺ T cell compartment enriched for naïve and effector-memory subsets with elevated expression of early activation genes (CD69, FOS, JUN, HLA-DR) but deficient in cytotoxic programs. Flow cytometry confirmed heightened early activation marker expression on CD8⁺ T cells in non-responders. Conclusions: Pre-existing ZNF683⁺ effector CD8⁺ T cell clones are associated with robust cytotoxic potential, enhanced B cell interactions, and favorable clinical responses to BiTE therapy in B-ALL. Resistance is characterized by the absence of such clones and the predominance of early-activated, non-functional CD8⁺ T cell subsets, alongside increased Treg expansion. ZNF683 defines a transcriptionally competent effector state and may serve as both a predictive biomarker and mechanistic axis for stratification and enhancement of T cell–based immunotherapies.
Source: Blood
Authors: Linghui Zhou, Cheng Zu, Kexin Wang, Mingming Zhang, Shan Fu, Jingjing Feng, He Huang, Yongxian Hu
Institution: First Affiliated Hospital Zhejiang University
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7108440411
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