this review describes the current status of nk cell therapy for cancer treatment based on the effector function and releasing the inhibited state of nk cells in the cancer microenvironment. therefore, this review discusses the mechanism of nk cells in cancer treatment and the current situation of nk cell therapy in clinical practice. in addition, inhibitory leukocyte immunoglobulin-like receptor-1 (lir-1) is also expressed on nk cells binding to hla-g, which complements kir and cd94/nkg2a in the recognition of hla class i molecules . cd56dim subsets constitute the majority of nk cells in circulation (blood, lung, and spleen) with stronger cytotoxicity and higher responsiveness to stimulation by cancer cells. as the development and progression of cancer are correlated with the dysfunction of nk cells, enhancing the function of nk cells is necessary for anti-cancer immunity. in addition, treg cell membrane-bound tgfβ and soluble tgfβ in tme inhibit nk cell function and downregulate the expression of nkg2d in nk cells . in addition, the biological characteristics of nk cells and modification techniques for improving the efficacy of nk cell therapies are widely discussed. notably, lymphodepleting conditioning treatment contributes to the remarkable increase in endogenous il-15 levels essential for the expansion and persistence of donor nk cells .
moreover, the combination of cytokines and feeder cells can ensure more effective expansion and activation of nk cells . in addition to monotherapy, optimized il-2 therapies combined with nk cell infusion therapy are under investigation for stimulating the activity of nk cells in vivo. therefore, blocking inhibitory checkpoints is essential to reverse the incapacity of nk cells (figure 2). ligands of these receptors are highly expressed on cancer cells and are associated with nk cell exhaustion and unfavorable prognosis. deleting the expression of the cish gene could enhance the proliferation, ifn-γ production, and cytotoxicity of nk cells and inhibit solid tumor growth in mouse models. the function of nk cells in response to cancer cells. for the best efficacy, a series of strategies are used to enhance the expansion and function of nk cells ex vivo. the cd47 antibody combined with pd-l1 antibody could reverse the incapacity of nk cells and stimulate more effective anti-cancer immunity.
immunotherapy is an innovative approach for the treatment of cancer and is based on the idea of harnessing the immune system to target tumors. the activating nk cell receptors include a series of non-hla-specific receptors and co-receptors able to induce nk cell triggering by directly interacting with ligands overexpressed or expressed de novo on tumor-transformed or virus-infected cells (23–25). however, tumor cells frequently develop strategies to evade nk cell immunosurveillance including changes at the tumor cell level (e.g., abnormal expression of ligands for activating and inhibitory receptors) and changes in tumor microenvironment (e.g., immunosuppressive cytokines), resulting in tumor escape and cancer progression (12, 45–48). with regard to the combination of anti-nkg2a with pd-1/pd-l1 disrupting agents, a combination of monalizumab and durvalumab has been evaluated in a first-in-human dose-escalation/dose-expansion phase i trial in patients with metastatic microsatellite-stable colorectal cancer (mss-crc). the increased surface levels of tim-3 on nk cells in cancers induce nk cell impairments (61), while tim-3 blockade results in increased nk cell cytotoxicity both in vitro and ex vivo (59, 62, 63). although the specific role of lag-3 on nk cells remains to be fully clarified, this inhibitory immune checkpoint is currently considered a good target for immunotherapy because of its potential to activate both t and nk cells. the igg4 antibody lirilumab prevents inhibitory signals from pan-kir2d, increasing nk cell-mediated tumor killing of aml in vitro and in vivo (31). in addition, combination with nk cell immunotherapy could increase the response rate of treatments targeting t cells (figure 1 and table 1). the blockade of immune checkpoints in cancer immunotherapy. (2019) 41:101272. doi: 10.1016/j.smim.2019.03.004 13. kiessling r, klein e, pross h, wigzell h. “natural” killer cells in the mouse. doi: 10.1111/j.1744-313x.1986.tb01095.x 16. ljunggren hg, karre k. in search of the ‘missing self’: mhc molecules and nk cell recognition. role in cell activation and regulation of cytolytic function. doi: 10.1126/science.1198687 25. marcenaro e, dondero a, moretta a. multi-directional cross-regulation of nk cell function during innate immune responses. cd56brightcd16- killer ig-like receptor- nk cells display longer telomeres and acquire features of cd56dim nk cells upon activation. anti-kir antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-cd20 antibodies.
pd-1 mediates functional exhaustion of activated nk cells in patients with kaposi sarcoma. doi: 10.1172/jci99317 42. sun h, sun c. the rise of nk cell checkpoints as promising therapeutic targets in cancer immunotherapy. doi: 10.1158/2326-6066.cir-16-0391 48. chiossone l, vienne m, kerdiles ym, vivier e. natural killer cell immunotherapies against cancer: checkpoint inhibitors and more. a phase 1 study of lirilumab (antibody against killer immunoglobulin-like receptor antibody kir2d; iph2102) in patients with solid tumors and hematologic malignancies. the clinical significance of abnormal tim-3 expression on nk cells from patients with gastric cancer. doi: 10.1084/jem.176.2.327 66. sun h, sun c, xiao w. expression regulation of co-inhibitory molecules on human natural killer cells in response to cytokine stimulations. lag-3, tim-3, and tigit: co-inhibitory receptors with specialized functions in immune regulation. blockade of the checkpoint receptor tigit prevents nk cell exhaustion and elicits potent anti-tumor immunity. doi: 10.1080/2162402x.2018.1509819 76. matosevic s. viral and nonviral engineering of natural killer cells as emerging adoptive cancer immunotherapies. anti-leukemia activity of alloreactive nk cells in kir ligand-mismatched haploidentical hsct for pediatric patients: evaluation of the functional role of activating kir and redefinition of inhibitory kir specificity. cellular and molecular basis of haploidentical hematopoietic stem cell transplantation in the successful treatment of high-risk leukemias: role of alloreactive nk cells. doi: 10.1038/nri999 95. marcenaro e, carlomagno s, pesce s, della chiesa m, moretta a, sivori s. role of alloreactive kir2ds1(+) nk cells in haploidentical hematopoietic stem cell transplantation. prognostic value of pretransplantation positron emission tomography using fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high-dose chemotherapy and stem cell transplantation. the early expansion of anergic nkg2a(pos)/cd56(dim)/cd16(neg) natural killer represents a therapeutic target in haploidentical hematopoietic stem cell transplantation. doi: 10.3324/haematol.2017.186619 keywords: nk cells, nk cell receptors, immune checkpoint blockade, immunotherapy, solid tumors, hematological malignancies, adoptive nk cell therapy citation: minetto p, guolo f, pesce s, greppi m, obino v, ferretti e, sivori s, genova c, lemoli rm and marcenaro e (2019) harnessing nk cells for cancer treatment.
a cancer treatment approach known as immunotherapy has become popular in the medical field. in this case, immune cells are boosted for effective cell therapy, a new approach that uses immune cells to attack tumors, has emerged as one of the most promising breakthroughs in cancer treatment. in the last years, natural killer (nk) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and, .
nk cells are a treatment option for chemotherapy-resistant acute myeloid leukemia (aml). compared to other forms of cancer treatment, such as chemotherapy, radiation, and even other immunotherapies, nk cell therapy does not cause many side effects. patients tend to tolerate it well. nk cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. anti-tumor activities of adoptively transferred nk cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, glioblastoma, and metastatic colorectal cancer [33,34,35,36]. as cited, car nk cells re-directed against cancer cells carrying particular antigens, make a natural killer cells – or nk cells – are part of our immune system. they patrol our bodies for abnormal cells like cancer and destroy them. adoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells, .
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