Prostaglandin E2 Secreted by Thyroid Cancer Cells Contributes to Immune Escape Through the Suppression of Natural Killer (NK) Cell Cytotoxicity and NK Cell Differentiation

Park, Arum; Lee, Yunhee; Kim, Mi Sun; Kang, Young Ju; Park, Young-Jun; Jung, Hye Young; Kim, Tae-Don; Lee, Hee Gu; Choi, Inpyo; Yoon, Suk Ran

doi:10.3389/fimmu.2018.01859

Cited by 124 publications

(108 citation statements)

References 55 publications

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“…PGE2 produced by tumor cells, tumor-associated macrophages, and stromal cells (113)(114)(115) represents a key regulator of the NK cell activity for mesenchymal stem cell (MSC)-mediated regulation of NK cell activity (116), tumor-derived MSCs (T-MSCs) (117), and MDSCs (118). In addition, PGE2 produced by the thyroid cancer cell microenvironment suppresses NK cell cytotoxicity (119). PGE2 downregulates the expression of NKp30, NKp44, NKp46, and NKG2D by binding to Eprostanoid 2 (EP2) and EP4 receptors on NK cells (112), via a common cAMP-PKA signaling (120), thus resulting in the inhibition of cytotoxicity (116,121).…”

Section: Immunosuppressive Properties Of the Tme On Nk Cellsmentioning

confidence: 99%

Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors

et al. 2020

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Natural killer (NK) cells are a population of innate lymphoid cells playing a pivotal role in host immune responses against infection and tumor growth. These cells have a powerful cytotoxic activity orchestrated by an intricate network of inhibitory and activating signals. The importance of NK cells in controlling tumor growth and in mediating a robust anti-metastatic effect has been demonstrated in different experimental mouse cancer models. Consistently, high density of tumor-infiltrating NK cells has been linked with a good prognosis in multiple human solid tumors. However, there are also tumors that appear to be refractory to NK cell-mediated killing for the presence of an immunosuppressive microenvironment affecting NK cell function. Immunotherapeutic strategies aimed at restoring and increasing the cytotoxic activity of NK cells in solid tumors, including the adoptive transfer of NK and CAR-NK cells, are currently employed in preclinical and clinical studies. In this review, we outline recent advances supporting the direct role of NK cells in controlling expansion of solid tumors and their prognostic value in human cancers. We summarize the mechanisms adopted by cancer cells and the tumor microenvironment to affect NK cell function, and finally we evaluate current strategies to augment the antitumor function of NK cells for the treatment of solid tumors.

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Section: Immunosuppressive Properties Of the Tme On Nk Cellsmentioning

confidence: 99%

Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors

et al. 2020

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“…TGF-β affects the metabolism of NK cells [175] and reduces NKG2D and NKp30 expression [176]. PGE2 inhibits NK cell differentiation, cytotoxicity and NKp44 and NKp30 expression, and may interfere with the NK cell-mediated recruitment of dendritic cells at the tumor site [177,178]. IDO plays an immunosuppressive role by causing both tryptophan (Trp) shortage and increased production of the Trp catabolite kynurenine, which downregulates NKp46 and NKG2D expression [28,179].…”

Section: Immunosuppressionmentioning

confidence: 99%

Mechanisms of Resistance to NK Cell Immunotherapy

Sordo‐Bahamonde

Vitale

Lorenzo‐Herrero

et al. 2020

Cancers

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Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells.

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“…TGF-β, IL10 [56], VEGF [57], and prostaglandin E2 (PGE2) [58] are all recognized as major players in suppressing immunity using non-redundant mechanisms, including suppressing antitumor immunity of CTL, conventional dendritic cells, pDC, Natural killer cells, but supporting pro-tumor immunity of TAM, MDSC, Treg [59,60].…”

Section: The Influence Of Immunosuppressive Tumor Microenvironment (Tmentioning

confidence: 99%