Search

BACKGROUNDImmune 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.METHODSSingle-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.RESULTSThe 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.CONCLUSIONOur study provides real-world clinical evidence that PD-1 acts as a tumor suppressor for malignant T cells with oncogenic TCR activation.TRIAL REGISTRATIONClinicalTrials.gov (NCT03809767).FUNDINGThe 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.

Cutaneous T cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphoma distinguished by the presence of clonal malignant T cells. The heterogeneity of malignant T cells and the complex tumor microenvironment remain poorly characterized. With single-cell RNA analysis and bulk whole-exome sequencing on 19 skin lesions from 15 CTCL patients, we decipher the intra-tumor and inter-lesion diversity of CTCL patients and propose a multi-step tumor evolution model. We further establish a subtyping scheme based on the molecular features of malignant T cells and their pro-tumorigenic microenvironments: the T CyEM group, demonstrating a cytotoxic effector memory T cell phenotype, shows more M2 macrophages infiltration, while the T CM group, featured by a central memory T cell phenotype and adverse patient outcome, is infiltrated by highly exhausted CD8 + reactive T cells, B cells and Tregs with suppressive activities. Our results establish a solid basis for understanding the nature of CTCL and pave the way for future precision medicine for CTCL patients., (© 2022. The Author(s).)

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergo large-cell transformation (LCT) in the late stage, manifesting aggressive behavior, resistance to treatments, and poor prognosis, but the mechanisms involved remain unclear. To identify the molecular driver of LCT, we collected tumor samples from 133 MF patients and performed whole-transcriptome sequencing on 49 advanced-stage MF patients, followed by integrated copy number inference and genomic hybridization. Tumors with LCT showed unique transcriptional programs and enriched expressions of genes at chr7q. Paternally expressed gene 10 (PEG10), an imprinted gene at 7q21.3, was ectopically expressed in malignant T cells from LCT, driven by 7q21.3 amplification. Mechanistically, aberrant PEG10 expression increased cell size, promoted cell proliferation, and conferred treatment resistance by a PEG10/KLF2/NF-κB axis in in vitro and in vivo models. Pharmacologically targeting PEG10 reversed the phenotypes of proliferation and treatment resistance in LCT. Our findings reveal new molecular mechanisms underlying LCT and suggest that PEG10 inhibition may serve as a promising therapeutic approach in late-stage aggressive T-cell lymphoma., (© 2022 by The American Society of Hematology.)

Abstract: Cutaneous squamous cell carcinoma usually extends beyond the visible margin. Little is known about the predictors for cutaneous squamous cell carcinoma with subclinical extension in Chinese individuals. This study aimed to construct a nomogram for predicting the probability of subclinical extension of cutaneous squamous cell carcinoma in Chinese patients.A retrospective analysis was conducted using data from Mohs micrographic surgery-treated cutaneous squamous cell carcinoma patients at a single institution between December 1, 2009 and October 31, 2019. Subclinical extension was defined as a lesion requiring ≥ 2 Mohs stages or with final safe margins of ≥ 5 mm. A nomogram predicting the probability of subclinical extension was constructed using the predictors identified in multivariable analysis.Of 274 patients included, 119 (43.4%) had subclinical extension. In multivariable analysis, male sex (odds ratio [OR], 2.45; 95% confidence interval [CI], 1.40-4.29; P = .002), lesions on mucocutaneous areas (OR, 3.71; 95% CI, 1.34-10.32; P = .012) and extremities (OR, 2.40; 95% CI, 1.20-4.78; P = .013), maximum diameter of 10 to 19 mm (OR, 14.15; 95% CI, 4.24-47.28; P < .001), and 20 to 29 mm (OR, 9.21; 95% CI, 2.80-30.29; P < .001) were associated with subclinical extension. A nomogram incorporating these 3 variables demonstrated promising predictive ability (C statistics = 0.78; 95% CI, 0.67-0.89).The nomogram incorporating sex, tumor location, and maximum diameter can provide individualized prediction for subclinical extension in Chinese patients with cutaneous squamous cell carcinoma. This information may help surgeons determine appropriate margins at the first Mohs stage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To study the significance of modified Mohs micrographic surgery in the treatment of cutaneous melanoma with the most appropriate margins., Methods: A total of 20 cases with cutaneous melanoma treated by the technique of modified Mohs micrographic surgery from July 2013 to July 2014 were reviewed. Modified Mohs micrographic surgery set safe margin according to Guideline of Chinese Melanoma Treatment (2011) first, and then decide whether to adopt wider margins according to the pathology of the resected margin. Data concerning the numbers of additional resection and the final total width of margins were analyzed and the latter compared with the initial margins., Results: Among 20 cases, 7 cases (35%) needed more than two resections to obtain a clear margin. The final widths of margin in 7 cases (35%) are different from the guideline., Conclusions: Modified Mohs micrographic surgery could ensure the thorough removal of primary tumor, while avoiding residual tumor as well as over-excision, which reflect the trend toward individualized treatment and minimally traumatic surgery.