Natural Killer Cells from Malignant Pleural Effusion Are Endowed with a Decidual-Like Proangiogenic Polarization

Abstract

Natural killer (NK) cells are crucial in tumor recognition and eradication, but their activity is impaired in cancer patients, becoming poorly cytotoxic. A particular type of NK cells, from the decidua, has low cytotoxicity and shows proangiogenic functions. We investigated whether NK cells from peripheral blood (PB) and pleural effusions of patients develop decidual-like NK phenotype and whether exposure to IL-2 can restore their killing ability in the presence of pleural fluids. NK cells from pleural effusion of patients with inflammatory conditions (iPE, n = 18), primary tumor (ptPE, n = 18), and metastatic tumor (tmPE, n = 27) acquired the CD56brightCD16− phenotype. NK cells from both ptPE and tmPE showed increased expression for the CD49a and CD69 decidual-like (dNK) markers and decreased levels of the CD57 maturation marker. NK from all the PE analyzed showed impaired degranulation capability and reduced perforin release. PE-NK cells efficiently responded to IL-2 stimulation in vitro. Addition of TGFβ or cell-free pleural fluid to IL-2 in the culture medium abrogated NK cell CD107a and IFNγ expression even in healthy donors (n = 14) NK. We found that tmPE-NK cells produce VEGF and support the formation of capillary-like structures in endothelial cells. Our results suggest that the PE tumor microenvironment can shape NK cell polarization towards a low cytotoxic, decidual-like, highly proangiogenic phenotype and that IL-2 treatment is not sufficient to limit this process.

Making cold malignant pleural effusions hot: driving novel immunotherapies

“…NK cells from human MPE exhibit poor cytotoxicity, having impaired degranulation and reduced perforin release. [122][123][124] In the malignant pleural environment, NK cells exhibit proangiogenic function, supporting capillary-like structures from recruited endothelial cells and produce angiogenic and vascular permeability inducing factors, including VEGF. 122 Interestingly, CD56 dim and CD56 bright NK cells isolated from human MPE cultured with IL-2 for 72 hours had potent antitumor cytolytic activity.…”

“…[122][123][124] In the malignant pleural environment, NK cells exhibit proangiogenic function, supporting capillary-like structures from recruited endothelial cells and produce angiogenic and vascular permeability inducing factors, including VEGF. 122 Interestingly, CD56 dim and CD56 bright NK cells isolated from human MPE cultured with IL-2 for 72 hours had potent antitumor cytolytic activity. 125 The same group found that IL-15 activated pleural effusion NK cells exhibited increased in vitro cytotoxicity and in vivo tumor clearance in mice.…”

Endometrial Cancer Immune Escape Mechanisms: Let Us Learn From the Fetal–Maternal Interface

“…Peripheral blood and tumor-infiltrated NK cells in cancer patients express the CD56 bright CD16 − CD49a + CD9 + phenotype (54,(58)(59)(60)(61), and they have compromised cytotoxicity (54,58,59,(61)(62)(63)(64). We have described a proangiogenic function in NK cells isolated from the peripheral blood and tumorinfiltrated cells of cancer patients (54,(58)(59)(60) and the expression of angiogenin, CXCR4/CXCL12, MMP2, MMP9, and tissue inhibitor for MMP (TIMP)-1 and TIMP-2 in NK cells from the peripheral blood and tumor-infiltrated cells of patients with colon cancer (59), which are molecules also secreted by dNK cells (55,(65)(66)(67). NK cells have been detected at low levels in the EC microenvironment (68); this study found significantly high levels of IL-1β and CXCL10 in the tumor, but low levels CXCL12, CCL27, and CCL21 as compared to the surrounding healthy tissue, and the NK cells in EC were compromised in cytotoxicity.…”

Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer

“…First evidence of NK cell functional plasticity in cancer highlighted the capability of TGF-β in the context of different advanced malignancies to induce a pro-angiogenic dNK cell phenotype of tumor infiltrating NK cells [76][77][78][79][80].…”