TY - JOUR
T1 - Spatially Resolved Tumor Microenvironment Predicts Treatment Outcomes in Relapsed/Refractory Hodgkin Lymphoma
AU - Aoki, Tomohiro
AU - Jiang, Aixiang
AU - Xu, Alexander
AU - Yin, Yifan
AU - Gamboa, Alicia
AU - Milne, Katy
AU - Takata, Katsuyoshi
AU - Miyata-Takata, Tomoko
AU - Chung, Shanee
AU - Rai, Shinya
AU - Wu, Shaocheng
AU - Warren, Mary
AU - Strong, Celia
AU - Goodyear, Talia
AU - Morris, Kayleigh
AU - Chong, Lauren C.
AU - Hav, Monirath
AU - Colombo, Anthony R.
AU - Telenius, Adele
AU - Boyle, Merrill
AU - Ben-Neriah, Susana
AU - Power, Maryse
AU - Gerrie, Alina S.
AU - Weng, Andrew P.
AU - Karsan, Aly
AU - Roth, Andrew
AU - Farinha, Pedro
AU - Scott, David W.
AU - Savage, Kerry J.
AU - Nelson, Brad H.
AU - Merchant, Akil
AU - Steidl, Christian
N1 - Publisher Copyright:
© 2024 American Society of Clinical Oncology.
PY - 2024/3/20
Y1 - 2024/3/20
N2 - PURPOSEAbout a third of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) succumb to their disease after high-dose chemotherapy followed by autologous stem-cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL.PATIENTS AND METHODSWe performed imaging mass cytometry (IMC) on 71 paired primary diagnostic and relapse biopsies using a marker panel specific to CHL biology. For each cell type in the TME, we calculated a spatial score measuring the distance of nearest neighbor cells to the malignant Hodgkin Reed Sternberg cells within the close interaction range. Spatial scores were used as features in prognostic model development for post-ASCT outcomes.RESULTSHighly multiplexed IMC data revealed shared TME patterns in paired diagnostic and early r/r CHL samples, whereas TME patterns were more divergent in pairs of diagnostic and late relapse samples. Integrated analysis of IMC and single-cell RNA sequencing data identified unique architecture defined by CXCR5+ Hodgkin and Reed Sternberg (HRS) cells and their strong spatial relationship with CXCL13+ macrophages in the TME. We developed a prognostic assay (RHL4S) using four spatially resolved parameters, CXCR5+ HRS cells, PD1+CD4+ T cells, CD68+ tumor-associated macrophages, and CXCR5+ B cells, which effectively separated patients into high-risk versus low-risk groups with significantly different post-ASCT outcomes. The RHL4S assay was validated in an independent r/r CHL cohort using a multicolor immunofluorescence assay.CONCLUSIONWe identified the interaction of CXCR5+ HRS cells with ligand-expressing CXCL13+ macrophages as a prominent crosstalk axis in relapsed CHL. Harnessing this TME biology, we developed a novel prognostic model applicable to r/r CHL biopsies, RHL4S, opening new avenues for spatial biomarker development.
AB - PURPOSEAbout a third of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) succumb to their disease after high-dose chemotherapy followed by autologous stem-cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL.PATIENTS AND METHODSWe performed imaging mass cytometry (IMC) on 71 paired primary diagnostic and relapse biopsies using a marker panel specific to CHL biology. For each cell type in the TME, we calculated a spatial score measuring the distance of nearest neighbor cells to the malignant Hodgkin Reed Sternberg cells within the close interaction range. Spatial scores were used as features in prognostic model development for post-ASCT outcomes.RESULTSHighly multiplexed IMC data revealed shared TME patterns in paired diagnostic and early r/r CHL samples, whereas TME patterns were more divergent in pairs of diagnostic and late relapse samples. Integrated analysis of IMC and single-cell RNA sequencing data identified unique architecture defined by CXCR5+ Hodgkin and Reed Sternberg (HRS) cells and their strong spatial relationship with CXCL13+ macrophages in the TME. We developed a prognostic assay (RHL4S) using four spatially resolved parameters, CXCR5+ HRS cells, PD1+CD4+ T cells, CD68+ tumor-associated macrophages, and CXCR5+ B cells, which effectively separated patients into high-risk versus low-risk groups with significantly different post-ASCT outcomes. The RHL4S assay was validated in an independent r/r CHL cohort using a multicolor immunofluorescence assay.CONCLUSIONWe identified the interaction of CXCR5+ HRS cells with ligand-expressing CXCL13+ macrophages as a prominent crosstalk axis in relapsed CHL. Harnessing this TME biology, we developed a novel prognostic model applicable to r/r CHL biopsies, RHL4S, opening new avenues for spatial biomarker development.
UR - http://www.scopus.com/inward/record.url?scp=85188027293&partnerID=8YFLogxK
U2 - 10.1200/JCO.23.01115
DO - 10.1200/JCO.23.01115
M3 - 学術論文
C2 - 38113419
AN - SCOPUS:85188027293
SN - 0732-183X
VL - 42
SP - 1077
EP - 1087
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 9
ER -
