Spatially Resolved Tumor Microenvironment Predicts Treatment Outcomes in Relapsed/Refractory Hodgkin Lymphoma

Area of Science:

• Hematologic Oncology
• Tumor Microenvironment Research
• Biomarker Discovery

Background:

• A significant portion of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) do not survive high-dose chemotherapy with autologous stem-cell transplantation (HDC/ASCT).
• Understanding the tumor microenvironment (TME) is crucial for identifying factors contributing to treatment failure in r/r CHL.

Purpose of the Study:

• To spatially characterize the TME ecosystems in r/r CHL.
• To discover novel biomarkers associated with treatment failure following HDC/ASCT in r/r CHL patients.

Main Methods:

• Imaging mass cytometry (IMC) was performed on 71 paired diagnostic and relapse biopsies from r/r CHL patients.
• Spatial scores were calculated based on the proximity of TME cells to malignant Hodgkin Reed Sternberg (HRS) cells.
• Prognostic models were developed using these spatial features to predict post-ASCT outcomes.

Main Results:

• IMC revealed distinct TME patterns between diagnostic and relapse samples, with greater divergence in late relapses.
• A unique TME architecture was identified, characterized by CXCR5+ HRS cells and their spatial association with CXCL13+ macrophages.
• A prognostic assay (RHL4S), incorporating four spatial parameters (CXCR5+ HRS cells, PD1+CD4+ T cells, CD68+ macrophages, CXCR5+ B cells), accurately stratified patients into high- and low-risk groups for post-ASCT outcomes.
• The RHL4S assay demonstrated validation in an independent cohort using multicolor immunofluorescence.

Conclusions:

• The interaction between CXCR5+ HRS cells and CXCL13+ macrophages represents a key crosstalk axis in relapsed CHL.
• The RHL4S assay, based on spatial TME biology, offers a novel prognostic tool for r/r CHL.
• This study opens new avenues for developing spatial biomarkers to predict treatment response in r/r CHL.