Infiltrating natural killer cells bind, lyse and increase chemotherapy efficacy in glioblastoma stem-like tumorospheres

Zidi

et al. 2023

Cells

Spheroids and organoids are important novel players in medical and life science research. They are gradually replacing two-dimensional (2D) cell cultures. Indeed, three-dimensional (3D) cultures are closer to the in vivo reality and open promising perspectives for academic research, drug screening, and personalized medicine. A large variety of cells and tissues, including tumor cells, can be the starting material for the generation of 3D cultures, including primary tissues, stem cells, or cell lines. A panoply of methods has been developed to generate 3D structures, including spontaneous or forced cell aggregation, air–liquid interface conditions, low cell attachment supports, magnetic levitation, and scaffold-based technologies. The choice of the most appropriate method depends on (i) the origin of the tissue, (ii) the presence or absence of a disease, and (iii) the intended application. This review summarizes methods and approaches for the generation of cancer spheroids and organoids, including their advantages and limitations. We also highlight some of the challenges and unresolved issues in the field of cancer spheroids and organoids, and discuss possible therapeutic applications.

Section: Methodological Options In Front Of Research On Anticancer Th...mentioning

confidence: 99%

Cancer Spheroids and Organoids as Novel Tools for Research and Therapy: State of the Art and Challenges to Guide Precision Medicine

Zidi

et al. 2023

Cells

“…Advances in chemotherapy, radiation, and neurosurgical procedures have increased survival of patients with brain tumors, but curative treatments are not yet available to malignancies like glioblastoma due to their recurrence and/or progression. NK cell-based therapies have shown efficacy in pre-clinical studies making them a promising treatment against glioblastoma ( 31 , 32 ). NK cell-based immunotherapies provide an allogeneic “off-the-shelf” alternative to T cell therapy since they do not cause graft-versus-host disease.…”

Section: Discussionmentioning

confidence: 99%

Cytokines impact natural killer cell phenotype and functionality against glioblastoma in vitro

Sivonen,

Sirviö,

Wojciechowski

et al. 2023

Front. Immunol.

ObjectiveNatural killer (NK) cells are a part of the innate immune system and first-line defense against cancer. Since they possess natural mechanisms to recognize and kill tumor cells, NK cells are considered as a potential option for an off-the-shelf allogeneic cell-based immunotherapy. Here, our objective was to identify the optimal cytokine-based, feeder-free, activation and expansion protocol for cytotoxic NK cells against glioblastoma in vitro.MethodsNK cells were enriched from human peripheral blood and expanded for 16 days with different activation and cytokine combinations. The expansion conditions were evaluated based on NK cell viability, functionality, expansion rate and purity. The cytotoxicity and degranulation of the expanded NK cells were measured in vitro from co‑cultures with the glioma cell lines U‑87 MG, U‑87 MG EGFR vIII, LN-229, U-118 and DK-MG. The best expansion protocols were selected from ultimately 39 different conditions: three magnetic cell‑selection steps (Depletion of CD3+ cells, enrichment of CD56+ cells, and depletion of CD3+ cells followed by enrichment of CD56+ cells); four activation protocols (continuous, pre-activation, re-activation, and boost); and four cytokine combinations (IL-2/15, IL‑21/15, IL‑27/18/15 and IL-12/18/15).ResultsThe expansion rates varied between 2-50-fold, depending on the donor and the expansion conditions. The best expansion rate and purity were gained with sequential selection (Depletion of CD3+ cells and enrichment of CD56+ cells) from the starting material and pre-activation with IL‑12/18/15 cytokines, which are known to produce cytokine-induced memory-like NK cells. The cytotoxicity of these memory-like NK cells was enhanced with re-activation, diminishing the donor variation. The most cytotoxic NK cells were produced when cells were boosted at the end of the expansion with IL-12/18/15 or IL-21/15.ConclusionAccording to our findings the ex vivo proliferation capacity and functionality of NK cells is affected by multiple factors, such as the donor, composition of starting material, cytokine combination and the activation protocol. The cytokines modified the NK cells' phenotype and functionality, which was evident in their reactivity against the glioma cell lines. To our knowledge, this is the first comprehensive comparative study performed to this extent, and these findings could be used for upscaling clinical NK cell manufacturing.

“…In GBM, NK cells, identified by the CD56 marker, are present in perivascular tumor regions but are often functionally impaired in the peripheral blood of GBM patients [ 150 ]. This impairment influences their capability for tumor cell lysis, which is also modulated by surface molecules on glioblastoma stem-like cells (GSLCs), including CD44, CD54, MHC class I, and PD-L1.…”

Section: Main Textmentioning

confidence: 99%

From glioma gloom to immune bloom: unveiling novel immunotherapeutic paradigms-a review

Regmi,

Wang,

Liu

et al. 2024

J Exp Clin Cancer Res

In tumor therapeutics, the transition from conventional cytotoxic drugs to targeted molecular therapies, such as those targeting receptor tyrosine kinases, has been pivotal. Despite this progress, the clinical outcomes have remained modest, with glioblastoma patients' median survival stagnating at less than 15 months. This underscores the urgent need for more specialized treatment strategies. Our review delves into the progression toward immunomodulation in glioma treatment. We dissect critical discoveries in immunotherapy, such as spotlighting the instrumental role of tumor-associated macrophages, which account for approximately half of the immune cells in the glioma microenvironment, and myeloid-derived suppressor cells. The complex interplay between tumor cells and the immune microenvironment has been explored, revealing novel therapeutic targets. The uniqueness of our review is its exhaustive approach, synthesizing current research to elucidate the intricate roles of various molecules and receptors within the glioma microenvironment. This comprehensive synthesis not only maps the current landscape but also provides a blueprint for refining immunotherapy for glioma, signifying a paradigm shift toward leveraging immune mechanisms for improved patient prognosis.