NK Cell Hyporesponsiveness: More Is Not Always Better

Frutoso, Marie; Mortier, Erwan

doi:10.3390/ijms20184514

Cited by 22 publications

(13 citation statements)

References 152 publications

(222 reference statements)

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“…Previous reports have shown that NK cells can become unresponsive on repeated administration of cytokines including IL-15 or sustained activation. 47 IL-15-resistance or antidrug antibodies are serious concerns. In this study, tumor-bearing mice received repeated doses of IL-15 or RLI (four times a week for 2 or 3 weeks) with antitumor activity and NK cell modulation observed.…”

Section: Discussionmentioning

confidence: 99%

IL-15 superagonist RLI has potent immunostimulatory properties on NK cells: implications for antimetastatic treatment

Desbois

Béal

Charrier

et al. 2020

J Immunother Cancer

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BackgroundAs the immune system is compromised in patients with cancer, therapeutic strategies to stimulate immunity appear promising, to avoid relapse and increase long-term overall survival. Interleukin-15 (IL-15) has similar properties to IL-2, but does not cause activation-induced cell death nor activation and proliferation of regulatory T cells (Treg), which makes it a serious candidate for anticancer immunotherapy. However, IL-15 has a short half-life and high doses are needed to achieve responses. Designed to enhance its activity, receptor-linker-IL-15 (RLI) (SO-C101) is a fusion molecule of human IL-15 covalently linked to the human IL-15Rα sushi+ domain currently assessed in a phase I/Ib clinical trial on patients with advanced/metastatic solid cancer.MethodsWe investigated the antimetastatic activity of RLI in a 4T1 mouse mammary carcinoma that spontaneously metastasizes and evaluated its immunomodulatory role in the metastatic lung microenvironment. We further characterized the proliferation, maturation and cytotoxic functions of natural killer (NK) cells in tumor-free mice treated with RLI. Finally, we explored the effect of RLI on human NK cells from healthy donors and patients with non-small cell lung cancer (NSCLC).ResultsRLI treatment displayed antimetastatic properties in the 4T1 mouse model. By characterizing the lung microenvironment, we observed that RLI restored the balance between NK cells and neutrophils (CD11b+Ly6GhighLy6Clow) that massively infiltrate lungs of 4T1-tumor bearing mice. In addition, the ratio between NK cells and Treg was strongly increased by RLI treatment. Further pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+CD27highKLRG1+mature NK cells. Finally, RLI demonstrated potent immunostimulatory properties on human NK cells by inducing proliferation and activation of NK cells from healthy donors and enhancing cytotoxic responses to NKp30 crosslinking in NK cells from patients with NSCLC.ConclusionsCollectively, our work demonstrates superior activity of RLI compared with rhIL-15 in modulating and activating NK cells and provides additional evidences for a therapeutic strategy using RLI as antimetastatic molecule.

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Section: Discussionmentioning

confidence: 99%

IL-15 superagonist RLI has potent immunostimulatory properties on NK cells: implications for antimetastatic treatment

Desbois

Béal

Charrier

et al. 2020

J Immunother Cancer

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“…Intriguingly, this pattern has implications for the use of NK cells in therapeutic settings and affects interpretations of how NK cells control virus infections and regulate autoimmunity. Additionally, NK cells act as a rheostat by removing activated CD4+ and CD8+ T cells in viral infections such as HIV and HCV, thus preventing T cell-mediated autoimmunity ( Lodoen and Lanier, 2005 ; Sun and Lanier, 2008 ; Frutoso and Mortier, 2019 ). Based on this knowledge we will comment on immune modulating treatment options that are being a proper strategy for the current COVID-19 crisis.…”

Section: Immunological Aspects Of Sars-cov2 Features Diagnosis and mentioning

confidence: 99%

Harnessing Memory NK Cell to Protect Against COVID-19

Soleimanian

Yaghobi

2020

Front. Pharmacol.

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The worldwide struggle against the coronavirus disease 2019 (COVID-19) as a public health crisis continues to sweep across the globe. Up to now, effective antiviral treatment against COVID-19 is not available. Therefore, throughout virus infections, a thorough clarification of the virus-host immune system interactions will be most probably helpful to encounter these challenges. Emerging evidence suggests that just like SARS and MERS, COVID-19 primarily suppresses the innate immune system, enabling its stable propagation during the early stage of infection. Consequently, proinflammatory cytokines and chemokines have been increasing during infection progression associated with severe lung pathology. It is imperative to consider hyper inflammation in vaccine designing, as vaccine-induced immune responses must have a protective role against infection without leading to immunopathology. Among the front-line responders to viral infections, Natural Killer (NK) cells have immense therapeutic potential, forming a bridge between innate and adaptive responses. A subset of NK cells exhibits putatively increased effector functions against viruses following pathogen-specific and immunization. Memory NK cells have higher cytotoxicity and effector activity, compared with the conventional NK cells. As a pioneering strategy, prompt accumulation and long-term maintenance of these memory NK cells could be an efficacious viral treatment. According to the high prevalence of human cytomegalovirus (HCMV) infection in the world, it remains to be determined whether HCMV adaptive NK cells could play a protective role against this new emerging virus. In addition, the new adaptive-like KIR+NKG2C+ NK cell subset (the adaptivelike lung tissue residue [tr]NK cell) in the context of the respiratory infection at this site could specifically exhibit the expansion upon COVID-19. Another aspect of NK cells we should note, utilizing modified NK cells such as allogeneic off-the-shelf CAR-NK cells as a state-of-the-art strategy for the treatment of COVID-19. In this line, we speculate introducing NKG2C into chimeric antigen receptors in NK cells might be a potential approach in future viral immunotherapy for emerging viruses. In this contribution, we will briefly discuss the current status and future perspective of NK cells, which provide to successfully exploit NK cellmediated antiviral activity that may offer important new tools in COVID-19 treatment.

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“…37 Furthermore, they proposed that these findings should inform IL-15 dosing strategies. Frutoso and Mortier, 17 and Frutoso and coworkers 38 provide excellent reviews of 'NK cell hyporesponsiveness: more is not always better'. They outline circumstances where providing additional IL-15 could actually be counterproductive and could lead to NK-cell hyporesponsiveness.…”

Section: Discussionmentioning

confidence: 99%

“…IL-15, a pleiotropic cytokine that stimulates the differentiation and proliferation of natural killer (NK) and CD8 T cells, is among the cytokines showing promise. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] IL-15 signals through a heterotrimeric receptor including the common gamma chain (γc) shared with IL-2, IL-4, IL-7, IL-9 and IL-21, the beta chain shared with IL-2 and a unique IL-15Rα chain. 4 14 15 IL-15Rα and IL-15 are produced in a coordinated fashion predominantly by activated monocytes and dendritic cells.…”

Section: Introductionmentioning

confidence: 99%

Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies

Dubois

Miljković

Fleisher

et al. 2021

J Immunother Cancer

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BackgroundFull application of cytokines as oncoimmunotherapeutics requires identification of optimal regimens. Our initial effort with intravenous bolus recombinant human interleukin-15 (rhIL-15) was limited by postinfusional reactions. Subcutaneous injection and continuous intravenous infusion for 10 days (CIV-10) provided rhIL-15 with less toxicity with CIV-10 giving the best increases in CD8+ lymphocytes and natural killer (NK) cells. To ease rhIL-15 administration, we shortened time of infusion. Treatment with rhIL-15 at a dose of 3–5 µg/kg as a 5-day continuous intravenous infusion (CIV-5) had no dose-limiting toxicities while effector cell stimulation was comparable to the CIV-10 regimen.MethodsEleven patients with metastatic cancers were treated with rhIL-15 CIV-5, 3 µg (n=4), 4 µg (n=3), and 5 µg/kg/day (n=4) in a phase I dose-escalation study (April 6, 2012).ResultsImpressive expansions of NK cells were seen at all dose levels (mean 34-fold), including CD56bright NK cells (mean 144-fold for 4 µg/kg), as well as an increase in CD8+ T cells (mean 3.38-fold). At 5 µg/kg/day, there were no dose-limiting toxicities but pulmonary capillary leak and slower patient recovery. This led to our choice of the 4 µg/kg as CIV-5 dose for further testing. Cytolytic capacity of CD56bright and CD56dim NK cells was increased by interleukin-15 assayed by antibody-dependent cellular cytotoxicity (ADCC), natural cytotoxicity and natural killer group 2D-mediated cytotoxicity. The best response was stable disease.ConclusionsIL-15 administered as CIV-5 substantially expanded NK cells with increased cytotoxic functions. Tumor-targeting monoclonal antibodies dependent on ADCC as their mechanism of action including alemtuzumab, obinutuzumab, avelumab, and mogamulizumab could benefit from those NK cell expansions and provide a promising therapeutic strategy.Trial registration numbersNCT01572493, NCT03759184, NCT03905135, NCT04185220 and NCT02689453.

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NK Cell Hyporesponsiveness: More Is Not Always Better

Cited by 22 publications

References 152 publications

IL-15 superagonist RLI has potent immunostimulatory properties on NK cells: implications for antimetastatic treatment

IL-15 superagonist RLI has potent immunostimulatory properties on NK cells: implications for antimetastatic treatment

Harnessing Memory NK Cell to Protect Against COVID-19

Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies

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