SPARC-positive macrophages are the superior prognostic factor in the microenvironment of diffuse large B-cell lymphoma and independent of MYC rearrangement and double-/triple-hit status.
Antineoplastic Combined Chemotherapy Protocols
Humans
Lymphoma, Large B-Cell, Diffuse
/ drug therapy
Macrophages
/ metabolism
Osteonectin
/ therapeutic use
Prognosis
Prospective Studies
Proto-Oncogene Proteins c-bcl-2
Proto-Oncogene Proteins c-bcl-6
Proto-Oncogene Proteins c-myc
/ genetics
Reproducibility of Results
Tumor Microenvironment
/ genetics
DLBCL
SPARC
biomarker
lymphoma
pathology
tumor microenvironment
Journal
Annals of oncology : official journal of the European Society for Medical Oncology
ISSN: 1569-8041
Titre abrégé: Ann Oncol
Pays: England
ID NLM: 9007735
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
28
06
2021
revised:
04
08
2021
accepted:
16
08
2021
pubmed:
27
8
2021
medline:
29
10
2021
entrez:
26
8
2021
Statut:
ppublish
Résumé
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC). We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME. The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, P[log rank] <0.001, P[trend] < 0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature [lymphoma-associated macrophage interaction signature (LAMIS)]. SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.
Sections du résumé
BACKGROUND
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC).
PATIENTS AND METHODS
We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME.
RESULTS
The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, P[log rank] <0.001, P[trend] < 0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature [lymphoma-associated macrophage interaction signature (LAMIS)].
CONCLUSIONS
SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.
Identifiants
pubmed: 34438040
pii: S0923-7534(21)04275-7
doi: 10.1016/j.annonc.2021.08.1991
pii:
doi:
Substances chimiques
MYC protein, human
0
Osteonectin
0
Proto-Oncogene Proteins c-bcl-2
0
Proto-Oncogene Proteins c-bcl-6
0
Proto-Oncogene Proteins c-myc
0
SPARC protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1400-1409Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Disclosure GAC received travel support/congress support from Novartis (not related to work); VP received travel support/congress support from AbbVie, Amgen, BMS, Gilead and Roche (not related to work); WK received grants from Amgen, Regeneron, and Takeda (not related to work). All remaining authors have declared no conflicts of interest.