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Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells.

ABSTRACT: Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from patients with GBM or healthy donors. We attributed this immune evasion tactic to direct cell-to-cell contact between GSCs and NK cells via αv integrin-mediated TGF-β activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling or with TGFBR2 gene-edited allogeneic NK cells prevented GSC-induced NK cell dysfunction and tumor growth. These findings reveal an important mechanism of NK cell immune evasion by GSCs and suggest the αv integrin/TGF-β axis as a potentially useful therapeutic target in GBM.

SUBMITTER: Shaim H

PROVIDER: S-EPMC8279586 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells.

Shaim Hila H Shanley Mayra M Basar Rafet R Daher May M Gumin Joy J Zamler Daniel B DB Uprety Nadima N Wang Fang F Huang Yuefan Y Gabrusiewicz Konrad K Miao Qi Q Dou Jinzhuang J Alsuliman Abdullah A Kerbauy Lucila N LN Acharya Sunil S Mohanty Vakul V Mendt Mayela M Li Sufang S Lu JunJun J Wei Jun J Fowlkes Natalie W NW Gokdemir Elif E Ensley Emily L EL Kaplan Mecit M Kassab Cynthia C Li Li L Ozcan Gonca G Banerjee Pinaki P PP Shen Yifei Y Gilbert April L AL Jones Corry M CM Bdiwi Mustafa M Nunez-Cortes Ana K AK Liu Enli E Yu Jun J Imahashi Nobuhiko N Muniz-Feliciano Luis L Li Ye Y Hu Jian J Draetta Giulio G Marin David D Yu Dihua D Mielke Stephan S Eyrich Matthias M Champlin Richard E RE Chen Ken K Lang Frederick F FF Shpall Elizabeth J EJ Heimberger Amy B AB Rezvani Katayoun K

The Journal of clinical investigation 20210701 14

Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral b ...[more]

PMID: 34138753

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Project description:BACKGROUND:The peculiar multiple myeloma microenvironment, characterized by up-regulated levels of several inflammatory chemokines, including the CXCR3 receptor ligands CXCL9 and CXCL10, limits NK cell positioning into the bone marrow by interfering with CXCR4 function. It is still unclear if the consequent reduced influx of transferred cells into the tumor represents a potential limiting factor for the success of NK cell-based adoptive therapy. We hypothesize that inhibition of CXCR3 function on NK cells will result in increased tumor clearance, due to higher NK cell bone marrow infiltration. METHODS:Since different activation protocols differently affect expression and function of homing receptors, we analyzed the bone marrow homing properties and anti-tumor efficacy of NK cells stimulated in vitro with two independent protocols. NK cells were purified from wild-type or Cxcr3-/- mice and incubated with IL-15 alone or with a combination of IL-12, IL-15, IL-18 (IL-12/15/18). Alternatively, CXCR3 function was neutralized in vivo using a specific blocking antibody. NK cell functional behavior and tumor growth were analyzed in bone marrow samples by FACS analysis. RESULTS:Both activation protocols promoted degranulation and IFN-γ production by donor NK cells infiltrating the bone marrow of tumor-bearing mice, although IL-15 promoted a faster but more transient acquisition of functional capacities. In addition, IL-15-activated cells accumulated more in the bone marrow in a short time but showed lower persistence in vivo. Targeting of CXCR3 increased the bone marrow homing capacity of IL-15 but not IL12/15/18 activated NK cells. This effect correlated with a superior and durable myeloma clearance capacity of transferred cells in vivo. CONCLUSIONS:Our results demonstrate that in vitro activation affects NK cell anti-myeloma activity in vivo by regulating their BM infiltration. Furthermore, we provided direct evidence that CXCR3 restrains NK cell anti-tumor capacity in vivo according to the activation protocol used, and that the effects of NK cell-based adoptive immunotherapy for multiple myeloma can be improved by increasing their bone marrow homing through CXCR3 inhibition.

Dataset Information

Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells.

Publications

Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells.

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