Hyperprogression of Cutaneous T Cell Lymphoma After Anti-PD-1 Treatment

Authors

Yumei Gao
Simeng Hu
Ruoyan Li
Shanzhao Jin
Fengjie Liu
Xiangjun Liu
Yingyi Li
Yicen Yan
Weiping Liu
Jifang Gong
Shuxia Yang
Ping Tu
Lin Shen
Fan Bai
Yang Wang

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

Comments

Trial Registration: ClinicalTrials.gov (NCT03809767)

DOI

10.1172/jci.insight.164793

PMID

36649072

PMCID

PMC9977500

PubMedCentral® Posted Date

February 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes