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Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV^± cancer.

ABSTRACT: Numerous studies are exploring the use of cell adoptive therapies to treat hematological malignancies as well as solid tumors. However, there are numerous factors that dampen the immune response, including viruses like human immunodeficiency virus. In this study, we leverage human-derived microphysiological models to reverse-engineer the HIV-immune system interaction and evaluate the potential of memory-like natural killer cells for HIV⁺ head and neck cancer, one of the most common tumors in patients living with human immunodeficiency virus. Here, we evaluate multiple aspects of the memory-like natural killer cell response in human-derived bioengineered environments, including immune cell extravasation, tumor penetration, tumor killing, T cell dependence, virus suppression, and compatibility with retroviral medication. Overall, these results suggest that memory-like natural killer cells are capable of operating without T cell assistance and could simultaneously destroy head and neck cancer cells as well as reduce viral latency.

SUBMITTER: Ayuso JM

PROVIDER: S-EPMC10590421 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV<sup>±</sup> cancer.

Ayuso Jose M JM Farooqui Mehtab M Virumbrales-Muñoz María M Denecke Katheryn K Rehman Shujah S Schmitz Rebecca R Guerrero Jorge F JF Sanchez-de-Diego Cristina C Campo Sara Abizanda SA Maly Elizabeth M EM Forsberg Matthew H MH Kerr Sheena C SC Striker Robert R Sherer Nathan M NM Harari Paul M PM Capitini Christian M CM Skala Melissa C MC Beebe David J DJ

Nature communications 20231021 1

Numerous studies are exploring the use of cell adoptive therapies to treat hematological malignancies as well as solid tumors. However, there are numerous factors that dampen the immune response, including viruses like human immunodeficiency virus. In this study, we leverage human-derived microphysiological models to reverse-engineer the HIV-immune system interaction and evaluate the potential of memory-like natural killer cells for HIV<sup>+</sup> head and neck cancer, one of the most common tu ...[more]

PMID: 37865647

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Project description:BackgroundHuman and mouse natural killer (NK) cells have been shown to develop memory-like function after short-term exposure to the cocktail of IL-12/15/18 or to overnight co-culture with some tumor cell lines. The resulting cells retain enhanced lytic ability for up to 7 days as well as after cryopreservation, and memory-like NK cells (mlNK) have been shown to induce complete remissions in patients with hematological malignancies. No single phenotype has been described for mlNK and the physiological changes induced by the short-term cytokine or tumor-priming which are responsible for these enhanced functions have not been fully characterized. Here, we have generated mlNK by cytokine and tumor-priming to find commonalities to better define the nature of NK cell "memory" in vitro and, for the first time, in vivo.MethodsWe initiated mlNK in vitro from healthy donors with cytokines (initiated cytokine-induced memory-like (iCIML)-NK) and by tumor priming (TpNK) overnight and compared them by high-dimensional flow cytometry, proteomic and metabolomic profiling. As a potential mechanism of enhanced cytolytic function, we analyzed the avidity of binding of the mlNK to NK-resistant tumors (z-Movi). We generated TpNK from healthy donors and from cancer patients to determine whether mlNK generated by interaction with a single tumor type could enhance lytic activity. Finally, we used a replication-incompetent tumor cell line (INKmune) to treat patients with myeloid leukaemias to potentiate NK cell function in vivo.ResultsTumor-primed mlNK from healthy donors and patients with cancer showed increased cytotoxicity against multiple tumor cell lines in vitro, analogous to iCIML-NK cells. Multidimensional cytometry identified distinct memory-like profiles of subsets of cells with memory-like characteristics; upregulation of CD57, CD69, CD25 and ICAM1. Proteomic profiling identified 41 proteins restricted to mlNK cells and we identified candidate molecules for the basis of NK memory which can explain how mlNK overcome inhibition by resistant tumors. Finally, of five patients with myelodysplastic syndrome or refractory acute myeloid leukemia treated with INKmune, three responded to treatment with measurable increases in NK lytic function and systemic cytokines.ConclusionsNK cell "memory" is a physiological state associated with resistance to MHC-mediated inhibition, increased metabolic function, mitochondrial fitness and avidity to NK-resistant target cells.

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Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV^± cancer.

Publications

Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV<sup>±</sup> cancer.

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Dataset Information

Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV± cancer.

Publications

Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV<sup>±</sup> cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV^± cancer.