Harnessing NK Cells for Cancer Treatment

Minetto, Paola; Guolo, Fabio; Pesce, Silvia; Greppi, Marco; Obino, Valentina; Ferretti, Elisa; Sivori, Simona; Genova, Carlo; Lemoli, Roberto M.; Marcenaro, Emanuela

doi:10.3389/fimmu.2019.02836

Cited by 68 publications

(53 citation statements)

References 106 publications

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“…NK cells are innate immune cells with potent cytolytic activity against tumors and in addition act as regulatory cells for the immune system. Based on the interesting concept of utilizing such innate immune system effectors, the adoptive NK cell therapy or the use of monoclonal antibodies targeting the main NK cell immune checkpoints is being investigated 61 The clinical efficacy of T‐cell‐based immunotherapy (eg, PD‐1/PD‐L1 inhibitors) presents some limitations, including its inability to recognize and kill HLA‐I neg tumor cells. Blockade with NK cell checkpoint inhibitors reversing their functional block may overcome such limitations of T‐cell‐based immunotherapy, mainly against HLA‐I neg tumor targets 61 .…”

Section: Natural Killer (Nk) Cellsmentioning

confidence: 99%

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

et al. 2020

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Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD‐L1 expression on tumors, tumor‐infiltrating lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.

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Section: Natural Killer (Nk) Cellsmentioning

confidence: 99%

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

et al. 2020

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“…In NK-cell based immunotherapy maximal NK cell activation is usually pursued; however, the higher is the activation and aggressiveness of NK cells, the higher will be the upregulation of mechanisms aimed to keep them under control either through immune checkpoint inhibitory receptors or through activation induced cell death mediated by death receptors such as TNF receptor family members or LFA-1 [6,17,44,82], which finally damp NK cell effectiveness. Moreover, although the maximal activation of the highly cytotoxic CD56 dim NK cells could be exploitable against tumour cells, it should be kept in mind that an excessive NK stimulation can easily lead to detrimental autoaggressive reactions [104].…”

Section: Resultsmentioning

confidence: 99%

“…The possibility of expanding and harnessing NK cells for cancer treatment led both to the development of NK adoptive transfer immunotherapies and to the use of monoclonal antibodies targeting the NK cell activating and inhibitory receptors [1,2,[4][5][6]56,57]. Nowadays several efforts are addressed to study and manipulate NK immune checkpoints, while data on synergistic cooperation induced by different NK surface activating receptors on distinct NK cell subsets are still incomplete.…”

Section: Discussionmentioning

confidence: 99%

“…Natural killer (NK) cells are large granular cytotoxic lymphocytes considered part of the innate immune system. They provide rapid responses against virally infected and tumour cells; for these features, NK cells have been successfully employed in several immunotherapeutic strategies [1][2][3][4][5][6]. NK cells express both activating and inhibitory receptors and the balance between their signalling plays an important role in self-tolerance and in NK cell activity [2,7,8].…”

Section: Introductionmentioning

confidence: 99%

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Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

Zamai

Zotto

Buccella

et al. 2020

Cells

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The NK cell population is characterized by distinct NK cell subsets that respond differently to the various activating stimuli. For this reason, the determination of the optimal cytotoxic activation of the different NK cell subsets can be a crucial aspect to be exploited to counter cancer cells in oncologic patients. To evaluate how the triggering of different combination of activating receptors can affect the cytotoxic responses of different NK cell subsets, we developed a microbead-based degranulation assay. By using this new assay, we were able to detect CD107a+ degranulating NK cells even within the less cytotoxic subsets (i.e., resting CD56bright and unlicensed CD56dim NK cells), thus demonstrating its high sensitivity. Interestingly, signals delivered by the co-engagement of NKp46 with 2B4, but not with CD2 or DNAM-1, strongly cooperate to enhance degranulation on both licensed and unlicensed CD56dim NK cells. Of note, 2B4 is known to bind CD48 hematopoietic antigen, therefore this observation may provide the rationale why CD56dim subset expansion correlates with successful hematopoietic stem cell transplantation mediated by alloreactive NK cells against host T, DC and leukemic cells, while sparing host non-hematopoietic tissues and graft versus host disease. The assay further confirms that activation of LFA-1 on NK cells leads to their granule polarization, even if, in some cases, this also takes to an inhibition of NK cell degranulation, suggesting that LFA-1 engagement by ICAMs on target cells may differently affect NK cell response. Finally, we observed that NK cells undergo a time-dependent spontaneous (cytokine-independent) activation after blood withdrawal, an aspect that may strongly bias the evaluation of the resting NK cell response. Altogether our data may pave the way to develop new NK cell activation and expansion strategies that target the highly cytotoxic CD56dim NK cells and can be feasible and useful for cancer and viral infection treatment.

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“…Augmenting the function of natural killer cells or adoptive transfer of NK cells have shown some clinical benefit as immunotherapy [ 64 , 65 , 66 , 67 ]. Unlike T cells, NK cells do not depend on MHC Class I expression to recognize tumor cells [ 67 ]. There are numerous activating and inhibiting receptors on NK cells that constantly interact with other cells [ 64 ].…”

Section: Hurdles Of Immunotherapymentioning

confidence: 99%

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

et al. 2020

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Cancer treatment has evolved tremendously in the last few decades. Immunotherapy has been considered to be the forth pillar in cancer treatment in addition to conventional surgery, radiotherapy, and chemotherapy. Though immunotherapy has resulted in impressive response, it is generally limited to a small subset of patients. Understanding the mechanisms of resistance toward cancer immunotherapy may shed new light to counter that resistance. In this review, we highlighted and summarized two major hurdles (recognition and attack) of cancer elimination by the immune system. The mechanisms of failure of some available immunotherapy strategies were also described. Moreover, the significance role of immune compartment for various established cancer treatments were also elucidated in this review. Then, the mechanisms of combinatorial treatment of various conventional cancer treatment with immunotherapy were discussed. Finally, a strategy to improve immune cancer killing by characterizing cancer immune landscape, then devising treatment based on that cancer immune landscape was put forward.

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Harnessing NK Cells for Cancer Treatment

Cited by 68 publications

References 106 publications

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

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