Monocytes and the 38kDa-antigen of mycobacterium tuberculosis modulate natural killer cell activity and their cytolysis directed against ovarian cancer cell lines

Gottschalk, Nina; Lang, Stephan; Singh, Mahavir; Brandau, Sven

doi:10.1186/1471-2407-12-451

Cited by 6 publications

(4 citation statements)

References 29 publications

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“…Our own previous studies have revealed that ovarian cancer cells show predominant resistance to NK cell-mediated natural cytotoxicity [24,32]. Cetuximab was able to overcome natural NK cell resistance significantly, but the addition of EGFR-specific TKIs did not further augment this ADCC mechanism.…”

Section: Introductionmentioning

confidence: 97%

EGFR-Specific Tyrosine Kinase Inhibitor Modifies NK Cell-Mediated Antitumoral Activity against Ovarian Cancer Cells

Mallmann-Gottschalk

Sax

Lang

et al. 2019

IJMS

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The adverse prognosis of most patients with ovarian cancer is related to recurrent disease caused by resistance to chemotherapeutic and targeted therapeutics. Besides their direct activity against tumor cells, monoclonal antibodies and tyrosine kinase inhibitors (TKIs) also influence the antitumoral activity of immune cells, which has important implications for the design of immunotherapies. In this preclinical study, we treated different ovarian cancer cell lines with anti-epidermal growth factor receptor (EGFR) TKIs and co-incubated them with natural killer (NK) cells. We studied treatment-related structural and functional changes on tumor and immune cells in the presence of the anti-EGFR antibody cetuximab and investigated NK-mediated antitumoral activity. We show that long-term exposure of ovarian cancer cells to TKIs leads to reduced responsiveness of intrinsically sensitive cancer cells over time. Inversely, neither long-term treatment with TKIs nor cetuximab could overcome the intrinsic resistance of certain ovarian cancer cells to anti-EGFR agents. Remarkably, tumor cells pretreated with anti-EGFR TKIs showed increased sensitivity towards NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In contrast, the cytokine secretion of NK cells was reduced by TKI sensitization. Our data suggest that sensitization of tumor cells by anti-EGFR TKIs differentially modulates interactions with NK cells. These data have important implications for the design of chemo-immuno combination therapies in this tumor entity.

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Section: Introductionmentioning

confidence: 97%

EGFR-Specific Tyrosine Kinase Inhibitor Modifies NK Cell-Mediated Antitumoral Activity against Ovarian Cancer Cells

Mallmann-Gottschalk

Sax

Lang

et al. 2019

IJMS

Self Cite

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“…Epidemiological studies showed a correlation between immunological parameters and long-term survival in neoplastic patients [11]. Immunotherapeutic approaches based on the use of bacterial components such as the BCG or a lipid A derivative of LPS (OM-174-DP) have been proposed to increase the efficacy of standard treatments in different malignances including ovarian cancer [30,31]. It is of note however, that our present data, together with previous studies, suggest the existence of a complex tumor microenvironment that would impair the attack of immune effectors such as NK cells.…”

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confidence: 99%

TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

et al. 2014

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We analyzed the functional outcome of the interaction between tumor-associated macrophages (TAMs) and natural killer (NK) cells. TAMs from ascites of ovarian cancer patients displayed an alternatively activated functional phenotype (M2) characterized by a remarkably high frequency and surface density of membrane-bound IL-18. Upon TLR engagement, TAMs acquired a classically activated functional phenotype (M1), released immunostimulatory cytokines (IL-12, soluble IL-18), and efficiently triggered the cytolytic activity of NK cells. TAMs also induced the release of IFN-γ from NK cells, which however was significantly lower compared with that induced by in vitro-polarized M2 cells. Most tumor-associated NK cells displayed a CD56 bright , CD16 neg or CD56 bright , CD16 dim phenotype, and very poor cytolytic activities, despite an increased expression of the activation marker CD69. They also showed downregulation of DNAM-1, 2B4, and NTB-A activating receptors, and an altered chemokine receptor repertoire. Importantly however, when appropriately stimulated, NK cells from the patients, including those cells isolated from ascites, efficiently killed autologous TAMs that expressed low, "nonprotective" levels of HLA class I molecules. Overall, our data show the existence of a complex tumor microenvironment in which poorly cytolytic/immature NK cells deal with immunosuppressive tumor-educated macrophages.Keywords: Human r Natural killer cells r Ovarian cancer r Tumor-associated macrophages Additional supporting information may be found in the online version of this article at the publisher's web-site [3][4][5][6]. Tumor and stromal cells produce chemokines such as CCL2 that recruit monocytes from peripheral blood. Once in tissue, the tumor microenvironment would prevent their differentiation into DCs while promoting differentiation into macrophages. Moreover, it would skew the macrophage polarization toward a proangiogenic/immunoregulatory M2-like phenotype with tumor-promoting properties. Notably, most studies have established a correlation between high numbers of tumorassociated macrophages (TAMs) within a tumor and poor prognosis [7][8][9]. Thus, an attractive novel clinical approach could be to identify factors able to revert TAMs into macrophages with M1 tumor-suppressive properties.Other innovative therapeutic protocols aim at increasing the function of immune effector cells with antitumor capabilities. Natural killer (NK) cells are appealing candidates for cancer immunotherapy [10,11] Results TAMs express high amounts of mIL-18TAMs were purified from ascitic fluids of patients affected by ovarian carcinoma (Table 1) and analyzed by flow cytometry for the expression of a large panel of cell surface markers ( Fig. 1 and Supporting Information Fig. 1). The results were compared with those obtained using in vitro IL-4-polarized M2 cells derived from peripheral blood monocytes of healthy donors. According to the gene expression profile analyses [19,20], the surface phenotype of TAMs closely resembled that of M2 cells (S...

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“…Using several cancer cell lines, we have previously demonstrated that PDSLCs exhibit lower MHC-class I expression, whereas well-differentiated tumors exhibit much higher expression of surface MHC-class I [ 14 , 85 , 86 ]. To understand the role of MHC-class I in susceptibility to NK cell-mediated cytotoxicity against ovarian tumors, we have previously used seven ovarian tumor cell lines: OVCAR3 [ 87 , 88 , 89 , 90 ], OVCAR4 [ 91 , 92 , 93 ], OVCAR8 [ 94 , 95 , 96 ], SKOV3 [ 77 , 97 , 98 ], Kuramochi [ 94 , 99 ], CaOV3 [ 77 , 100 , 101 , 102 ], and OAW28 [ 86 , 103 , 104 ]. There was a great correlation between the levels of MHC-class I expression and targeting by NK cells.…”

Section: The Role Of Mhc-class I and Ii Expression On Ovarian Tumors ...mentioning

confidence: 99%

Exploring the Potential of Natural Killer Cell-Based Immunotherapy in Targeting High-Grade Serous Ovarian Carcinomas

Kaur,

Sanghu,

Memarzadeh

et al. 2024

Vaccines

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High-grade serous ovarian cancers (HGSOCs) likely consist of poorly differentiated stem-like cells (PDSLCs) and differentiated tumor cells. Conventional therapeutics are incapable of completely eradicating PDSLCs, contributing to disease progression and tumor relapse. Primary NK cells are known to effectively lyse PDSLCs, but they exhibit low or minimal cytotoxic potential against well-differentiated tumors. We have introduced and discussed the characteristics of super-charged NK (sNK) cells in this review. sNK cells, in comparison to primary NK cells, exhibit a significantly higher capability for the direct killing of both PDSLCs and well-differentiated tumors. In addition, sNK cells secrete significantly higher levels of cytokines, especially those known to induce the differentiation of tumors. In addition, we propose that a combination of sNK and chemotherapy could be one of the most effective strategies to eliminate the heterogeneous population of ovarian tumors; sNK cells can lyse both PDSLCs and well-differentiated tumors, induce the differentiation of PDSLCs, and could be used in combination with chemotherapy to target both well-differentiated and NK-induced differentiated tumors.

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Monocytes and the 38kDa-antigen of mycobacterium tuberculosis modulate natural killer cell activity and their cytolysis directed against ovarian cancer cell lines

Cited by 6 publications

References 29 publications

EGFR-Specific Tyrosine Kinase Inhibitor Modifies NK Cell-Mediated Antitumoral Activity against Ovarian Cancer Cells

EGFR-Specific Tyrosine Kinase Inhibitor Modifies NK Cell-Mediated Antitumoral Activity against Ovarian Cancer Cells

TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

Exploring the Potential of Natural Killer Cell-Based Immunotherapy in Targeting High-Grade Serous Ovarian Carcinomas

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