Multiple myeloma impairs bone marrow localization of effector natural killer cells by altering the chemokine microenvironment

Andrea Ponzetta, Giorgia Benigni, Fabrizio Antonangeli, Giuseppe Sciumè, Emilio Sanseviero, Alessandra Zingoni, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Angela Santoni, Giovanni Bernardini

Research output: Contribution to journalArticlepeer-review

Abstract

Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice. Herein we report that the number of KLRG1- NK cells endowed with potent effector function rapidly and selectively decreases in bone marrow during multiple myeloma growth, this correlating with decreased bone marrow NK cell degranulation in vivo. Altered NK cell subset distribution was dependent on skewed chemokine/chemokine receptor axes in the multiple myeloma microenvironment, with rapid downmodulation of the chemokine receptor CXCR3 onNKcells, increased CXCL9 and CXCL10, and decreased CXCL12 expression in bone marrow. Similar alterations in chemokine receptor/chemokine axes were observed in patients with multiple myeloma. Adoptive transfer experiments demonstrated that KLRG1- NK cell migration to the bone marrow was more efficient in healthy than multiple myeloma-bearing mice. Furthermore, bone marrow localization of transferred CXCR3-deficient NK cells with respect to wild type was enhanced in healthy and multiple myeloma-bearing mice, suggesting that CXCR3 restrains bone marrow NK cell trafficking. Our results indicate that multiple myeloma-promoted CXCR3 ligand upregulation together with CXCL12 downmodulation act as exit signals driving effector NK cells outside the bone marrow, thus weakening the antitumor immune response at the primary site of tumor growth.

Original languageEnglish
Pages (from-to)4766-4777
Number of pages12
JournalCancer Research
Volume75
Issue number22
DOIs
Publication statusPublished - Nov 15 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'Multiple myeloma impairs bone marrow localization of effector natural killer cells by altering the chemokine microenvironment'. Together they form a unique fingerprint.

Cite this