Student and Faculty Publications
Publication Date
2-22-2023
Journal
JCI Insight
Abstract
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.
Keywords
Adolescent, Humans, Lymphoma, T-Cell, Cutaneous, Protein Kinase C-theta, Receptors, Antigen, T-Cell, Signal Transduction, Skin Neoplasms, Immunotherapy, Lymphomas
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Sciences Commons, Oncology Commons
Comments
Supplementary Materials
Data Availability Statement
PMID: 36649072