NK cells to cure cancer

Vito, Clara Di; Mikulak, Joanna; Zaghi, Elisa; Pesce, Silvia; Marcenaro, Emanuela; Mavilio, Domenico

doi:10.1016/j.smim.2019.03.004

Cited by 81 publications

(72 citation statements)

References 375 publications

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“…38 Natural killer cells have become an increasingly important target for cancer immunotherapy since they have demonstrated to mediate successful and efficient anti-tumor responses. 39,40 They play an important role in pancreatic cancer as we have shown here, and although depletion of NK cells did not have as drastic an effect on response to CD40 and IL-15 combination as CD8 + T cells, it is likely that they still play an important role in this therapy given the increase in both their activation and numbers in the tumor. This is an important observation since a higher frequency of NK cells is clearly linked to better survival.…”

Section: Discussionmentioning

confidence: 53%

Novel combination immunotherapy for pancreatic cancer: potent anti‐tumor effects with CD40 agonist and interleukin‐15 treatment

et al. 2020

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Objectives With the poorest 5‐year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. We sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin‐15 and tested its potential in pancreatic cancer. Methods Response to this combination regimen was assessed in pancreatic ductal adenocarcinoma mouse models, and a thorough analysis of the tumor microenvironment was performed. Results We demonstrated profound reduction in tumor growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented 8‐fold dose reduction of CD40 agonist without losing any efficacy. RNAseq analysis showed involvement of natural killer (NK) cell‐ and T‐cell‐mediated anti‐tumor responses and the importance of antigen‐presenting cell pathways. This combination resulted in enhanced infiltration of tumors by both T cells and NK cells, as well as a striking increase in the ratio of CD8+ T cells over Tregs. We also observed a significant increase in numbers of dendritic cells (DCs) in tumor‐draining lymph nodes, particularly CD103+ DCs with cross‐presentation potential. A critical role for CD8+ T cells and involvement of NK cells in the anti‐tumor effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin‐15 and the CD40 agonist were combined. Conclusion These novel preclinical data support initiation of a first‐in‐human clinical trial with this combination immunotherapy strategy in pancreatic cancer.

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Section: Discussionmentioning

confidence: 53%

Novel combination immunotherapy for pancreatic cancer: potent anti‐tumor effects with CD40 agonist and interleukin‐15 treatment

et al. 2020

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“…The prognostic value of NK cells for a longer survival requires further investigation. Third, NK cells can be divided into CD56 dim and CD56 bright cells [32], which have different antitumor activities; however, this study did not analyze these two subsets, because our laboratory did not separate them during the test. Fourth, the length of follow-up for R0 resection patients was relatively shorter; we did not collect data on disease-free survival or recurrence-free survival, which are more appropriate for describing the association in patients who underwent an R0 resection.…”

Section: Discussionmentioning

confidence: 97%

Prognostic value of peripheral blood natural killer cells in colorectal cancer

Tang

Xie

et al. 2020

BMC Gastroenterol

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Background: The association between natural killer (NK) cells and survival in colorectal cancer (CRC) patients remains controversial. This study aimed to clarify the prognostic value of peripheral blood NK cells in CRC patients.Methods: A total of 447 CRC patients who underwent radical surgery and chemotherapy were retrospectively analyzed. Cox regression analyses were used to identify independent prognostic indicators. Correlation between NK cell percentage and other clinicopathological features (gender, age, histological grade, tumor stage, immune cells, and inflammatory indicators) was analyzed. The prognostic values of the combinations of NK cell percentage and other clinicopathological features were also determined. Results: Multivariate Cox regression analysis revealed that NK cell percentage in the peripheral blood was an independent prognostic indicator in CRC patients. A higher percentage of NK cells indicated a longer survival time than a lower percentage. NK cell percentage was positively correlated to the T and B lymphocyte counts and negatively correlated to the patients' age and albumin levels. With an area of 0.741 under a receiver operating characteristic curve, NK cells have a moderate predictive value for 3rd-year survival in CRC. This area increased to 0.851 by combining NK cell percentage with the B lymphocyte count. Elderly patients and those at an advanced clinical stage presented a lower percentage of NK cells than younger patients and those at an early clinical stage.Conclusions: This study demonstrated that NK cells in the blood were an independent predictor of survival in CRC patients, and the combined count of NK cells and B lymphocytes could increase the prognostic value.

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“…Both the killing and immune-regulative functions of NK cells depend on a balance of activating or inhibiting signals that originate from NK receptors (NKRs) (activating NKR-aNKR and inhibitory NKR -iNKR-, respectively). The iNKRs include the human leucocyte antigens (HLA) class I-specific Killer Ig-like receptors (KIRs) recognizing allotypic determinants shared by groups of classical HLA-ABC alleles (Moretta et al, 1996), the leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) that is specific for different HLA-class I molecules (Cosman et al, 1997), and the CD94/NKG2A heterodimer specific for HLA-E (Braud et al, 1998) ad well as additional non-HLA-I specific inhibitory receptors, including programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), Tcell immunoglobulin domain and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), and CD96 (Di Vito et al, 2019). The activating NKRs (aKIRs) include non-HLA-specific receptors such as NCRs (NKp30, NKp44 and NKp46), NKG2D, DNAM-1, NKp80, CD59, NTB-A, and 2B4 (Moretta et al, 2001) as well as the activating HLA class I-specific Killer Ig-like receptors and the HLA-E specific CD94/NKG2C heterodimer.…”

Section: Nk Cells As Innate Immune Cells With a Key Role In Fighting mentioning

confidence: 99%

“…For example, IL-2-based immunotherapy allows NK cells to override inhibitory signals from acute myeloid leukemia (AML) blasts (Hallner et al, 2019), and recently, immunotherapies based on the use of therapeutic monoclonal antibodies specific for iNKRs, in particular anti-pan-KIR2D (lirilumab) (Romagne et al, 2009;Kohrt et al, 2014;Vey et al, 2018) and anti-NKG2A (monalizumab), have been developed (André et al, 2018;Tinker et al, 2019;Zaghi et al, 2019). These agents efficiently disrupt the interaction between these NK cell immune checkpoints and their ligands, and will in this way enable NK cells to efficiently kill also HLA-I + tumor cells (Chiossone et al, 2017;Di Vito et al, 2019).…”

Section: Nk Cells As Innate Immune Cells With a Key Role In Fighting mentioning

confidence: 99%

“…In addition, the microenvironment of chronic infections and tumors may lead to NK cell phenotypic changes and impairment of NK cell functions (Bi and Tian, 2017). The most frequently NK cell phenotypic changes are represented by downregulation of the aNKRs expression (Costello et al, 2002;Romero et al, 2006;Carlsten et al, 2009;Pesce et al, 2015;Han et al, 2018;Poznanski and Ashkar, 2019) and/or upregulation/de novo expression of iNKRs (Carlsten et al, 2009;Di Vito et al, 2019;Sanchez-Correa et al, 2019). In fact, it has been unveiled that besides T lymphocytes also NK cells can express PD-1, an immune checkpoint specific for the PD-L1/2 molecules often displayed on the surface of tumor cells (Pesce et al, 2019b).…”

Section: Nk Cells As Innate Immune Cells With a Key Role In Fighting mentioning

confidence: 99%

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miRNAs in NK Cell-Based Immune Responses and Cancer Immunotherapy

Pesce

Greppi

Ferretti

et al. 2020

Front. Cell Dev. Biol.

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The incidence of certain forms of tumors has increased progressively in recent years and is expected to continue growing as life expectancy continues to increase. Tumor-infiltrating NK cells may contribute to develop an anti-tumor response. Optimized combinations of different cancer therapies, including NK cell-based approaches for targeting tumor cells, have the potential to open new avenues in cancer immunotherapy. Functional inhibitory receptors on NK cells are needed to prevent their attack on healthy cells. Nevertheless, disruption of inhibitory receptors function on NK cells increases the cytotoxic capacity of NK cells against cancer cells. MicroRNAs (miRNAs) are small non-coding RNA molecules that target mRNA and thus regulate the expression of genes involved in the development, maturation, and effector functions of NK cells. Therapeutic strategies that target the regulatory effects of miRNAs have the potential to improve the efficiency of cancer immunotherapy. Interestingly, emerging evidence points out that some miRNAs can, directly and indirectly, control the surface expression of immune checkpoints on NK cells or that of their ligands on tumor cells. This suggests a possible use of miRNAs in the context of anti-tumor therapy. This review provides the current overview of the connections between miRNAs and regulation of NK cell functions and discusses the potential of these miRNAs as innovative biomarkers/targets for cancer immunotherapy.

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NK cells to cure cancer

Cited by 81 publications

References 375 publications

Novel combination immunotherapy for pancreatic cancer: potent anti‐tumor effects with CD40 agonist and interleukin‐15 treatment

Novel combination immunotherapy for pancreatic cancer: potent anti‐tumor effects with CD40 agonist and interleukin‐15 treatment

Prognostic value of peripheral blood natural killer cells in colorectal cancer

miRNAs in NK Cell-Based Immune Responses and Cancer Immunotherapy

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