Immune Checkpoint Blockade: A Strategy to Unleash the Potential of Natural Killer Cells in the Anti-Cancer Therapy

Grottoli, Melania; Carrega, Paolo; Zullo, Lodovica; Dellepiane, Chiara; Rossi, Giovanni; Parisi, Francesca; Barletta, Giulia; Zinoli, Linda; Coco, Simona; Alama, Angela; Marconi, Silvia; Parodi, Monica; Orecchia, Paola; Bassi, Sara; Vitale, Massimo; Mingari, Maria Cristina; Pfeffer, Ulrich; Genova, Carlo; Pietra, Gabriella

doi:10.3390/cancers14205046

Cited by 9 publications

(7 citation statements)

References 107 publications

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“…The results showed that the proportion of Tregs in the mice treated with ES@CuO+PD‐1 was significantly lower than that in the control mice, while the proportion of CD3 + CD4 + T cells did not change among the groups (Figure S20 , Supporting Information). Natural killer (NK) cells are a subset of lymphocytes responsible for antitumor activity; [ 39 , 40 ] therefore, tumor‐infiltrating NK cells were also analyzed. The results demonstrated that more NK cells infiltrated the TME after treatment with ES@CuO+PD‐1 therapy (Figure 6F,G ).…”

Section: Resultsmentioning

confidence: 99%

Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy

Lu,

Chen,

Lin

et al. 2024

Advanced Science

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The induction of cuproptosis, a recently identified form of copper‐dependent immunogenic cell death, is a promising approach for antitumor therapy. However, sufficient accumulation of intracellular copper ions (Cu2+) in tumor cells is essential for inducing cuproptosis. Herein, an intelligent cuproptosis‐inducing nanosystem is constructed by encapsulating copper oxide (CuO) nanoparticles with the copper ionophore elesclomol (ES). After uptake by tumor cells, ES@CuO is degraded to release Cu2+ and ES to synergistically trigger cuproptosis, thereby significantly inhibiting the tumor growth of murine B16 melanoma cells. Moreover, ES@CuO further promoted cuproptosis‐mediated immune responses and reprogrammed the immunosuppressive tumor microenvironment by increasing the number of tumor‐infiltrating lymphocytes and secreted inflammatory cytokines. Additionally, combining ES@CuO with programmed cell death‐1 (PD‐1) immunotherapy substantially increased the antitumor efficacy in murine melanoma. Overall, the findings of this study can lead to the use of a novel strategy for cuproptosis‐mediated antitumor therapy, which may enhance the efficacy of immune checkpoint inhibitor therapy.

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Section: Resultsmentioning

confidence: 99%

Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy

Lu,

Chen,

Lin

et al. 2024

Advanced Science

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“…CD56 bright NK cells are considered efficient cytokine producers and are the main NK cell population infiltrating cancer tissues, while the CD56 dim NK cell subset (the most mature and 90% of peripheral blood NK cells) is able to mediate a strong cytotoxic response upon the engagement of activating receptors and even to exert antibody-dependent cellmediated cytotoxicity (ADCC) [36]. Among NK cells, we detected that both CD56 dim NK and CD56 bright NK were higher in patients with DC compared to patients with PD.…”

Section: Discussionmentioning

confidence: 99%

Circulating Natural Killer Cells as Prognostic Value for Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Correlation with Sarcopenia

Tenuta

Pandozzi

Sciarra

et al. 2023

Cancers

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Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of tumors. Natural killer (NK) cells can play an important role in cancer immune surveillance. The aim of this prospective observational study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICIs in order to identify predictive factors for better survival outcomes. Methods: Forty-seven stage IV NSCLC patients were enrolled. Patients underwent baseline (T0) and longitudinal (T1) evaluations after ICIs. Peripheral immune blood cell counts were analyzed using flow cytometry. Results: Basal levels of CD3−CD56+ NK cells were higher in patients with controlled disease (DC) compared to progression disease (PD) patients (127 cells/µL vs. 27.8 cells/µL, p < 0.001). Lower NK cell values were independent prognostic factors for shorter overall survival (OS) (HR 0.992; 95% CI 0.987–0.997, p < 0.001) and progression-free survival (PFS) (HR 0.988; 95% CI 0.981–0.994, p < 0.001). During the longitudinal evaluation, CD3−CD56+ NK cells (138.1 cells/µL vs. 127 cells/µL, p = 0.025) and CD56bright NK cells (27.4 cells/µL vs. 18.1 cells/µL, p = 0.034) significantly increased in the DC group. Finally, lower values of CD3−CD56+ NK cells (28.3 cells/µL vs. 114.6 cells/µL, p = 0.004) and CD56dim NK cells (13.2 cells/µL vs. 89.4 cells/µL, p < 0.001) were found in sarcopenic patients compared to patients without sarcopenia. Conclusions: Peripheral NK cells could represent a non-invasive and useful tool to predict ICI therapy response in NSCLC patients, and the association of low NK cell levels with sarcopenia deserves even more attention in clinical evaluation.

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“…A study found that the infusion of allogeneic donor NK cells in 15 patients with NSCLC led to partial tumor shrinkage in two patients and stable disease in six patients 27 . In NSCLC patients with nivolumab treatment, higher absolute numbers of circulating NK cells were associated with longer OS 28 . Several human studies have demonstrated that PD‐1 expression on NK cells is present in cancer patients and weakens their antitumor effects.…”

Section: Discussionmentioning

confidence: 99%

“… 27 In NSCLC patients with nivolumab treatment, higher absolute numbers of circulating NK cells were associated with longer OS. 28 Several human studies have demonstrated that PD‐1 expression on NK cells is present in cancer patients and weakens their antitumor effects. However, the use of immune checkpoint inhibitors can enhance the effect of NK cells.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the efficacy and feasibility of combined therapy of PD‐L1‐enhanced exogenous peripatetic adoptive natural killer (NK) cells in combination with antiangiogenic targeted therapy in the treatment of extensive‐stage small cell lung cancer

Wang,

Zhang,

Cao

et al. 2023

Thoracic Cancer

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A 67‐year‐old male patient presented with extensive‐stage small cell lung cancer with the primary lesion located in the right upper lung, accompanied by multiple metastases to the pleura and abdominal cavity with enlarged mediastinal lymph nodes. A combination therapy approach was used to target the patient's multiple systemic metastases after localized radiotherapy. The approach involved adoptive transfer of programmed death ligand 1 (PD‐L1) enhanced exogenous natural killer (NK) cells, along with antiangiogenic treatment. Allogeneic cord blood NK cells were infused back into the patient over two consecutive days. On the first day, the treatment was followed by a dose of 1200 mg of atezolizumab. Subsequently, the patient received a daily dose of 10 mg of anlotinib administered orally for 14 days. This was followed by a 7‐day break, and each cycle lasted 21 days. After delivering localized radiation to the primary lesion in the right lung and metastatic mediastinal lymph nodes, complete remission was achieved in the local lesion, effectively avoiding the risk of superior vena cava syndrome. Following six cycles of combined therapy, most of the metastatic lesions had disappeared, and the remaining metastatic lesions had significantly reduced in size. The recent therapeutic effect resulted in partial remission. The combination therapy of immune checkpoint inhibitor PD‐L1‐enhanced exogenous adoptive transfer NK cells, along with antiangiogenic targeted treatment, demonstrated a satisfactory short‐term effect, with disappearance of most of the metastases and noticeable shrinkage in the remaining metastatic lesions.

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Immune Checkpoint Blockade: A Strategy to Unleash the Potential of Natural Killer Cells in the Anti-Cancer Therapy

Cited by 9 publications

References 107 publications

Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy

Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy

Circulating Natural Killer Cells as Prognostic Value for Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Correlation with Sarcopenia

Investigation of the efficacy and feasibility of combined therapy of PD‐L1‐enhanced exogenous peripatetic adoptive natural killer (NK) cells in combination with antiangiogenic targeted therapy in the treatment of extensive‐stage small cell lung cancer

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