| Title | Hyperprogression of cutaneous T cell lymphoma after anti-PD-1 treatment |
| Authors | 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 |
| Affiliation | Peking Univ First Hosp, Dept Dermatol & Venereol, 8 Xishiku St, Beijing 100034, Peoples R China Beijing Key Lab Mol Diag Dermatoses, Beijing, Peoples R China Natl Clin Res Ctr Skin & Immune Dis, Beijing, Peoples R China Peking Univ, Biomed Pioneering Innovat Ctr BIOPIC, 5 Yiheyuan Rd, Beijing 100871, Peoples R China Peking Univ, Sch Life Sci, 5 Yiheyuan Rd, Beijing 100871, Peoples R China Peking Univ, Acad Adv Interdisciplinary Studies AAIS, Beijing, Peoples R China Peking Univ, Peking Univ Tsinghua Univ Natl Inst Biol Sci Joint, Beijing, Peoples R China Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge, England BioMap Beijing Intelligence Technol Ltd, Block C Informat Ctr Haidian Dist, Beijing, Peoples R China Peking Univ, Dept Lymphoma, Key Lab Carcinogenesis & Translat Res, Minist Educ,Canc Hosp & Inst, Beijing, Peoples R China Peking Univ, Key Lab Carcinogenesis & Translat Res, Minist Educ Beijing, Dept Gastrointestinal Oncol,Canc Hosp & Inst, Beijing, Peoples R China Peking Univ, Beijing Adv Innovat Ctr Genom ICG, Beijing, Peoples R China Peking Univ First Hosp, Ctr Translat Canc Res, Beijing, Peoples R China |
| Keywords | SEZARY-SYNDROME PROGRAMMED DEATH-1 PKC-THETA ACTIVATION PD-1 EXPRESSION ORGANIZATION PATHWAY |
| Issue Date | 22-Feb-2023 |
| Publisher | 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 PKCO; PKCO is a key player in the T cell activation/NF-KB pathway. PRKCQ amplification led to high expressions of PKCO and p-PKCO (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). |
| URI | http://hdl.handle.net/20.500.11897/672084 |
| DOI | 10.1172/jci.insight.164793 |
| Indexed | SCI(E) |
| Appears in Collections: | 第一医院 生物医学前沿创新中心 生命科学学院 前沿交叉学科研究院 北京肿瘤医院 |
