Single-cell transcriptome analysis reveals T-cell exhaustion in denosumab-treated giant cell tumor of bone

Front Immunol. 2022 Sep 12;13:934078. doi: 10.3389/fimmu.2022.934078. eCollection 2022.

Abstract

Denosumab (DMAB), a human monoclonal antibody against the receptor activator of the nuclear factor-kappa B ligand, is used for the treatment for unresectable giant cell tumor of bone (GCTB). However, little is known about the molecular and functional characteristics of GCTB-infiltrating lymphocytes after DMAB treatment. Here, we performed single-cell RNA sequencing and immunostaining assays to delineate the immune landscape of GCTB in the presence and absence of DMAB. We found that exhausted CD8+ T cells were preferentially enriched in DMAB-treated GCTB. A distinct M2-skewed type of tumor-associated macrophages (TAMs) comprises the majority of GCTB TAMs. We identified cytokines, including interleukin-10, and inhibitory receptors of M2 TAMs as important mediators of CD8+ T cell exhaustion. We further revealed that DMAB treatment notably increased the expression levels of periostin (POSTN) in GCTB cells. Furthermore, POSTN expression was transcriptionally regulated by c-FOS signaling and correlated with GCTB recurrence in patients after DMAB treatment. Collectively, our findings reveal that CD8+ T-cells undergo unappreciated exhaustion during DMAB therapy and that GCTB cell-derived POSTN educates TAMs and establishes a microenvironmental niche that facilitates GCTB recurrence.

Keywords: Denosumab; RANKL; T-cell exhaustion; giant cell tumor of bone; periostin; single-cell RNA-seq.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Neoplasms* / drug therapy
  • Bone Neoplasms* / genetics
  • Bone Neoplasms* / pathology
  • CD8-Positive T-Lymphocytes / pathology
  • Denosumab / pharmacology
  • Denosumab / therapeutic use
  • Gene Expression Profiling
  • Giant Cell Tumor of Bone* / drug therapy
  • Giant Cell Tumor of Bone* / genetics
  • Giant Cell Tumor of Bone* / pathology
  • Humans
  • Interleukin-10
  • Ligands

Substances

  • Ligands
  • Interleukin-10
  • Denosumab