Multiplexed spatial profiling of Hodgkin Reed-Sternberg cell neighborhoods in classic Hodgkin lymphoma.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Maryam Pourmaleki, Caitlin J Jones, Sabrina D Mellinghoff, Brian D Greenstein, Priyadarshini Kumar, Miguel Foronda, Daniel A Navarrete, Carl Campos, Mikhail Roshal, Nikolaus Schultz, Sohrab P Shah, Andrea Schietinger, Nicholas D Socci, Travis J Hollmann, Ahmet Dogan, Ingo K Mellinghoff

TLDR

  • This study looked at the relationship between Hodgkin Reed-Sternberg (HRS) cells and their surroundings in a type of cancer called classic Hodgkin lymphoma (cHL). The study used special imaging and testing to see how the HRS cells interact with their surroundings and what genes are turned on or off in these cells. The study found that the HRS cells in cHL are linked with certain immune cells and signaling pathways that could help the cancer cells survive and grow. The study also found that the HRS cells in some cHL tumors are clustered together and that these clusters are associated with certain immune cells. The study's findings could help doctors develop new treatments for cHL that target these immune cells and signaling pathways.

Abstract

Classic Hodgkin lymphoma (cHL) is a B cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of non-malignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown. We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV) positive and EBV-negative cHL tumors. We show that MHC-I expression on HRS cells is associated with immune inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD-1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T cell excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T cells high neighborhoods harboring HRS cells with augmented proliferative capacity. Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.

Overview

  • The study aims to investigate the molecular determinants governing the relationship between Hodgkin Reed-Sternberg (HRS) cells and their proximal microenvironment in classic Hodgkin lymphoma (cHL).
  • The study used spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV) positive and EBV-negative cHL tumors. The primary objective is to identify the immune inflamed neighborhoods and potential immune escape mechanisms in cHL.

Comparative Analysis & Findings

  • The study identified that MHC-I expression on HRS cells is associated with immune inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD-1 and VISTA).
  • The study also found spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T cell excluded neighborhoods in a subset of EBV-negative tumors. Additionally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T cells high neighborhoods harboring HRS cells with augmented proliferative capacity.

Implications and Future Directions

  • The study's findings suggest that HRS cell properties are linked with distinct immunophenotypes and potential immune escape mechanisms in cHL. These findings could have significant implications for the development of new immunotherapies targeting immune checkpoints and regulatory T cells in cHL. Future research could focus on validating these findings in larger cohorts and exploring the role of other immune cells and signaling pathways in cHL.
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