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Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatment

BACKGROUND: Immune checkpoint blockade is an emerging treatment for T cell non-Hodgkin’s lymphoma (T-NHL), but some patients with T-NHL have experienced hyperprogression with undetermined mechanisms upon anti–PD-1 therapy. METHODS: Single-cell RNA-Seq, whole-genome sequencing, whole-exome sequencing...

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Detalles Bibliográficos
Autores principales: Gao, Yumei, Hu, Simeng, Li, Ruoyan, Jin, Shanzhao, Liu, Fengjie, Liu, Xiangjun, Li, Yingyi, Yan, Yicen, Liu, Weiping, Gong, Jifang, Yang, Shuxia, Tu, Ping, Shen, Lin, Bai, Fan, Wang, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977500/
https://www.ncbi.nlm.nih.gov/pubmed/36649072
http://dx.doi.org/10.1172/jci.insight.164793
Descripción
Sumario:BACKGROUND: Immune checkpoint blockade is an emerging treatment for T cell non-Hodgkin’s lymphoma (T-NHL), but some patients with T-NHL have experienced hyperprogression with undetermined mechanisms upon anti–PD-1 therapy. METHODS: Single-cell RNA-Seq, whole-genome sequencing, whole-exome sequencing, and functional assays were performed on primary malignant T cells from a patient with advanced cutaneous T cell lymphoma who experienced hyperprogression upon anti–PD-1 treatment. RESULTS: The patient was enrolled in a clinical trial of anti–PD-1 therapy and experienced disease hyperprogression. Single-cell RNA-Seq revealed that PD-1 blockade elicited a remarkable activation and proliferation of the CD4(+) malignant T cells, which showed functional PD-1 expression and an exhausted status. Further analyses identified somatic amplification of PRKCQ in the malignant T cells. PRKCQ encodes PKCθ; PKCθ is a key player in the T cell activation/NF-κB pathway. PRKCQ amplification led to high expressions of PKCθ and p-PKCθ (T538) on the malignant T cells, resulting in an oncogenic activation of the T cell receptor (TCR) signaling pathway. PD-1 blockade in this patient released this signaling, derepressed the proliferation of malignant T cells, and resulted in disease hyperprogression. CONCLUSION: Our study provides real-world clinical evidence that PD-1 acts as a tumor suppressor for malignant T cells with oncogenic TCR activation. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03809767). FUNDING: The National Natural Science Foundation of China (81922058), the National Science Fund for Distinguished Young Scholars (T2125002), the National Science and Technology Major Project (2019YFC1315702), the National Youth Top-Notch Talent Support Program (283812), and the Peking University Clinical Medicine plus X Youth Project (PKU2019LCXQ012) supported this work.