Dysfunctions of innate and adaptive immune tumor microenvironment in Waldenström macroglobulinemia

Danka Cholujova, Gabor Beke, Zachary R. Hunter, Teru Hideshima, Ludmila Flores, Tatiana Zeleznikova, Denisa Harrachova, Lubos Klucar, Merav Leiba, Lubos Drgona, Steven P. Treon, Efstathios Kastritis, David M. Dorfman, Kenneth C. Anderson, Jana Jakubikova

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by malignant lymphoplasmacytic cells in the bone marrow (BM). To dissect the pathophysiology of WM, we evaluated clonal cells by mapping of B cell lymphomagenesis with adaptive and innate immune tumor microenvironment (TME) in the BM of WM patients using mass cytometry (CyTOF). In-depth immunophenotypic profiling of WM cells exhibited profound expansion of clonal cells in both unswitched and switched memory B cells and also plasma cells with aberrant expression variations. WM B lymphomagenesis was associated with reduction of most B cell precursors assessed with the same clonally restricted light chain and phenotypic changes. The immune TME was infiltrated by mature monocytes, neutrophils and adaptive T cells, preferentially subsets of effector T helper, effector CTL and effector memory CTL cells that were associated with superior overall survival (OS), in contrast to progenitors of T cells and myeloid/monocytic lineage subsets that were suppressed in WM cohort. Moreover, decrease in immature B and NKT cells was related to worse OS in WM patients. Innate and adaptive immune subsets of WM TME were modulated by immune checkpoints, including PD-1/PD-L1&PD-L2, TIGIT/PVR, CD137/CD137-L, CTLA-4, BTLA and KIR expression. The response of ibrutinib treatment to the reduction of clonal memory B cell was associated with high levels of immature B cells and effector memory CTL cells. Our study demonstrates that CyTOF technology is a powerful approach for characterizing the pathophysiology of WM at various stages, predicting patient risk and monitoring the effectiveness of treatment strategies.

Original languageEnglish
Pages (from-to)1947-1963
Number of pages17
JournalInternational Journal of Cancer
Volume152
Issue number9
DOIs
StatePublished - 1 May 2023
Externally publishedYes

Keywords

  • B cell lymphomagenesis
  • Waldenström macroglobulinemia
  • innate and adaptive immunity
  • mass cytometry
  • tumor microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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