Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells

Nham, Tina; Poznanski, Sophie M.; Fan, Isabella Y.; Shenouda, Mira M.; Chew, Marianne V.; Lee, Dean A.; Vahedi, Fatemeh; Karimi, Yalda; Butcher, Martin; Hirte, Hal W.; Ashkar, Ali A.

doi:10.1007/s00262-017-2112-x

Cited by 36 publications

(43 citation statements)

References 42 publications

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“…NK cells are highly enriched in the ascites collected from ovarian carcinoma patients but are mostly CD16 − and show a lack of cytotoxic function with diminished IFNγ production. 33,34 Similar changes and dysfunction were reported in NK cells isolated from patients with esophageal squamous cell carcinoma and non-small cell lung carcinoma, particularly in pleural effusion. 38,39 The downregulation of CD16 on NK cells has been shown to be driven by TGFβ and leads to conversion from cytotoxic to a more immunoregulatory phenotype similar to decidual NK cells.…”

Section: Discussionsupporting

confidence: 53%

“…Loss of CD16 expression has been reported on NK cells recovered from ovarian patient ascites and was connected to loss of cytotoxic function. 33,34 Interestingly, NK cells from animals treated with anti-PD-L1 also had greater frequencies of CD57 + NK cells (30 vs . 47%, p = 0.0014; Figure 4C) which have been correlated with memory-like phenotype and are associated in several studies with better outcomes and improved long-term survival across many tumor types.…”

Section: Resultsmentioning

confidence: 99%

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PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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Section: Discussionsupporting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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“…It has been previously reported that OC ascites NK cells have been described to exhibit lower expression of the activating markers NKp30, NKp46, NKG2D and DNAM-1 compared to healthy donor PB-NK cells [ 8 , 49 ]. In our study, we observed the same significantly lower expression of NKp30, NKp46 and DNAM-1 on OC ascites-derived NK cells compared to NK cells from benign peritoneal fluid.…”

Section: Discussionmentioning

confidence: 99%

Peritoneal NK cells are responsive to IL-15 and percentages are correlated with outcome in advanced ovarian cancer patients

et al. 2018

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The demonstration that ovarian carcinoma (OC) is an immunogenic disease, opens opportunities to explore immunotherapeutic interventions to improve clinical outcome. In this regard, NK cell based immunotherapy could be promising as it has been demonstrated that OC cells are susceptible to killing by cytokine-stimulated NK cells. Here, we evaluated whether percentage, phenotype, function and IL-15 responsiveness of ascites-derived natural killer (NK) cells is related to progression-free survival (PFS) and overall survival (OS) of advanced stage OC patients. Generally, a lower percentage of NK cells within the lymphocyte fraction was seen in OC ascites (mean 17.4 ± 2.7%) versus benign peritoneal fluids (48.1 ± 6.8%; p < 0.0001). Importantly, a higher CD56+ NK cell percentage in ascites was associated with a better PFS (p = 0.01) and OS (p = 0.002) in OC patients. Furthermore, the functionality of ascites-derived NK cells in terms of CD107a/IFN-γ activity was comparable to that of healthy donor peripheral blood NK cells, and stimulation with monomeric IL-15 or IL-15 superagonist ALT-803 potently improved their reactivity towards tumor cells. By showing that a higher NK cell percentage is related to better outcome in OC patients and NK cell functionality can be boosted by IL-15 receptor stimulation, a part of NK cell immunity in OC is further deciphered to exploit NK cell based immunotherapy.

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“…NK cells are capable of exerting anti-tumor activity and lysing tumor cells without prior sensitization in an HLA-unrestricted way in contrast to TILs, for example. It has been shown that it is possible to generate cytotoxic NK cells from the ascites of ovarian cancer patients 35. Clinical experiences are so far limited with low partial response and short duration of PFS 36…”

Section: Cell-based Therapymentioning

confidence: 99%

Immunotherapy in ovarian cancer: fake news or the real deal?

Marth¹,

Wieser

Tsibulak

et al. 2019

Int J Gynecol Cancer

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Cancer immunotherapy has emerged as one of the most promising approaches in oncology, and comprises the activation of the immune system to induce tumor immune surveillance or to reverse the tumor immune escape. Different therapeutic strategies for ovarian carcinoma have evolved over the years. Already 30 years ago, the first clinical studies focused on modulating the tumor cytokine network with special attention to interferon-mediated immune responses. With the exploration of specific tumor antigens such as NY-ESO-1, which is expressed in ovarian carcinoma and other malignancies, the development of therapeutic cancer vaccines has been pursued initiating the era of personalized anti-cancer medicine. Almost at the same time, the adoptive transfer of genetically modified autologous tumor-reactive T-cells occurred, but response rates in ovarian carcinoma were disappointing. Today, probably the most promising therapeutic approach in this context is the blockade of immune checkpoints, such as programed cell death protein 1 (PD-1) and one of its ligands (PD-L1) or cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4), which has demonstrated impressive response rates in malignant melanoma and non-small cell lung cancer. Despite increasing availability of treatment approaches that target tumor immune surveillance in ovarian carcinoma, selecting patient groups that particularly benefit from these treatment modalities is clinically challenging as predictive biomarkers are lacking. Here, we summarize different immunotherapy approaches in ovarian cancer and discuss why immunotherapy in ovarian cancer is still in its infancy.

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Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells

Cited by 36 publications

References 42 publications

PD-L1 blockade enhances anti-tumor efficacy of NK cells

PD-L1 blockade enhances anti-tumor efficacy of NK cells

Peritoneal NK cells are responsive to IL-15 and percentages are correlated with outcome in advanced ovarian cancer patients

Immunotherapy in ovarian cancer: fake news or the real deal?

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