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, a...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-02-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.164793 |
| _version_ | 1797634320140075008 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yumei Gao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:06:56Z |
| format | Article |
| id | doaj.art-b8fe779a45db4343a1bdf1bc83917b8f |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:56Z |
| publishDate | 2023-02-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-b8fe779a45db4343a1bdf1bc83917b8f2023-11-07T16:25:15ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-02-0184Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatmentYumei GaoSimeng HuRuoyan LiShanzhao JinFengjie LiuXiangjun LiuYingyi LiYicen YanWeiping LiuJifang GongShuxia YangPing TuLin ShenFan BaiYang WangBACKGROUND 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.https://doi.org/10.1172/jci.insight.164793Oncology |
| spellingShingle | 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 Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatment JCI Insight Oncology |
| title | Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatment |
| title_full | Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatment |
| title_fullStr | Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatment |
| title_full_unstemmed | Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatment |
| title_short | Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatment |
| title_sort | hyperprogression of cutaneous t cell lymphoma after anti pd 1 treatment |
| topic | Oncology |
| url | https://doi.org/10.1172/jci.insight.164793 |
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