Cutaneous T cell lymphoma atlas reveals malignant T2 cells supported by a B cell-rich tumor microenvironment.

in Nature immunology by Ruoyan Li, Johanna Strobl, Elizabeth F M Poyner, Aya Balbaa, Fereshteh Torabi, Pavel V Mazin, Nana-Jane Chipampe, Emily Stephenson, Ciro Ramírez-Suástegi, Vijaya Baskar Mahalingam Shanmugiah, Louis Gardner, Bayanne Olabi, Rowen Coulthard, Rachel A Botting, Nina Zila, Elena Prigmore, Nusayhah H Gopee, Marta A Chroscik, Efpraxia Kritikaki, Justin Engelbert, Issac Goh, Hon Man Chan, Harriet F Johnson, Jasmine Ellis, Victoria Rowe, Win Tun, Gary Reynolds, Dexin Yang, April Rose Foster, Laure Gambardella, Elena Winheim, Chloe Admane, Benjamin Rumney, Lloyd Steele, Laura Jardine, Julia Nenonen, Keir Pickard, Jennifer Lumley, Philip Hampton, Simeng Hu, Fengjie Liu, Xiangjun Liu, David Horsfall, Daniela Basurto-Lozada, Louise Grimble, Chris M Bacon, Sophie C Weatherhead, Hanna Brauner, Yang Wang, Fan Bai, Nick J Reynolds, Judith E Allen, Constanze Jonak, Patrick M Brunner, Sarah A Teichmann, Muzlifah Haniffa

TLDR

  • The study investigates the molecular mechanisms underlying a type of skin cancer called cutaneous T cell lymphoma (CTCL). The researchers used single-cell and spatial transcriptomics analysis of skin samples from CTCL patients, along with comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. They found that malignant CTCL cells co-opt T2 cell-immune gene programs, which are typically associated with allergic responses. The researchers modeled the tumor microenvironment to support the survival of these T2 cell-like tumor cells. They also found that CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. The study validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. The findings suggest that targeting T2 cell-immune gene programs and the tumor microenvironment could be potential therapeutic strategies for CTCL.

Abstract

Cutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (T2) cell-immune gene programs by malignant CTCL cells and modeling of the tumor microenvironment to support their survival. We identified MHC-IIfibroblasts and dendritic cells that can maintain T2 cell-like tumor cells. CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. Finally, we validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL.

Overview

  • The study investigates the molecular mechanisms underlying cutaneous T cell lymphoma (CTCL), specifically mycosis fungoides, a difficult-to-diagnose form of the disease. The researchers used single-cell and spatial transcriptomics analysis of skin samples from CTCL patients, along with comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. The primary objective of the study is to understand the immune gene programs co-opted by malignant CTCL cells and the tumor microenvironment that supports their survival. The study aims to provide diagnostic aids, potential biomarkers for disease staging, and therapeutic strategies for CTCL.

Comparative Analysis & Findings

  • The study reveals that malignant CTCL cells co-opt T helper 2 (T2) cell-immune gene programs, which are typically associated with allergic responses. The researchers modeled the tumor microenvironment to support the survival of these T2 cell-like tumor cells. They identified MHC-IIfibroblasts and dendritic cells that can maintain T2 cell-like tumor cells. CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. The study validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. The findings suggest that targeting T2 cell-immune gene programs and the tumor microenvironment could be potential therapeutic strategies for CTCL.

Implications and Future Directions

  • The study's findings provide valuable insights into the molecular mechanisms underlying CTCL and could lead to the development of new diagnostic aids, biomarkers for disease staging, and therapeutic strategies. The study highlights the importance of understanding the tumor microenvironment in CTCL and the potential role of T2 cell-immune gene programs in the disease. Future research could focus on developing targeted therapies that specifically target T2 cell-immune gene programs and the tumor microenvironment in CTCL. Additionally, further validation of the findings in larger patient cohorts and clinical trials is needed to establish the clinical relevance of the study's findings.
Read Full Article