High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment

SummaryTubo-ovarian high-grade serous cancer (HGSC) is unresponsive to immune checkpoint blockade despite significant frequencies of exhausted T cells. Here we applied mass cytometry to uncover decidual-like (dl)-NK cell subpopulations (CD56+CD9+CXCR3+KIR+CD3-CD16-) in chemo-naïve HGSC tumors that correlated with both tumor and transitioning epithelial-mesenchymal cell abundance. We showed different combinatorial expression patterns of ligands for activating and inhibitory NK receptors within the three HGSC tumor cell compartments; epithelial (E), transitioning epithelial-mesenchymal (EV) and mesenchymal (vimentin-expressing cells, V) with a more inhibitory ligand phenotype in V cells. When co-cultured with HGSC cell lines the NK-92 cell line acquired CD9 from tumor cells by trogocytosis with a resultant reduction in both anti-tumor cytokine production and cytotoxicity. Critically, a CD9 blocking antibody restored the killing activity of CD9+-NK-92 cells. These findings identify previously unrecognized mechanisms of immune suppression in HGSC. Furthermore, since CD9 is widely expressed in HGSC tumors it represents an important new therapeutic target with immediate relevance for NK immunotherapy.

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Cytokine-Induced Memory-Like NK Cells with High Reactivity against Acute Leukemia Blasts and Solid Tumor Cells Suitable for Adoptive Immunotherapy Approaches

Cancers ◽

10.3390/cancers13071577 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1577

Author(s):

Matteo Tanzi ◽

Michela Consonni ◽

Michela Falco ◽

Federica Ferulli ◽

Enrica Montini ◽

...

Keyword(s):

Acute Leukemia ◽

Nk Cells ◽

Tumor Cells ◽

Cell Function ◽

Nk Cell ◽

Autologous Tumor ◽

Lymphoid Leukemia ◽

Hematopoietic Stem ◽

Solid Malignancies

The limited efficacy of Natural Killer (NK) cell-based immunotherapy results in part from the suboptimal expansion and persistence of the infused cells. Recent reports suggest that the generation of NK cells with memory-like properties upon in vitro activation with defined cytokines might be an effective way of ensuring long-lasting NK cell function in vivo. Here, we demonstrate that activation with IL-12, IL-15 and IL-18 followed by a one-week culture with optimal doses of Interleukin (IL-2) and IL-15 generates substantial numbers of memory-like NK cells able to persist for at least three weeks when injected into NOD scid gamma (NSG) mice. This approach induces haploidentical donor-derived memory-like NK cells that are highly lytic against patients’ myeloid or lymphoid leukemia blasts, independent of the presence of alloreactive cell populations in the donor and with negligible reactivity against patients’ non-malignant cells. Memory-like NK cells able to lyse autologous tumor cells can also be generated from patients with solid malignancies. The anti-tumor activity of allogenic and autologous memory-like NK cells is significantly greater than that displayed by NK cells stimulated overnight with IL-2, supporting their potential therapeutic value both in patients affected by high-risk acute leukemia after haploidentical hematopoietic stem cell transplantation and in patients with advanced solid malignancies.

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