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Medulloblastoma rendered susceptible to NK-cell attack by TGF? neutralization.

ABSTRACT: BACKGROUND:Medulloblastoma (MB), the most common pediatric brain cancer, presents with a poor prognosis in a subset of patients with high risk disease, or at recurrence, where current therapies are ineffective. Cord blood (CB) natural killer (NK) cells may be promising off-the-shelf effector cells for immunotherapy due to their recognition of malignant cells without the need for a known target, ready availability from multiple banks, and their potential to expand exponentially. However, they are currently limited by immune suppressive cytokines secreted in the MB tumor microenvironment including Transforming Growth Factor ? (TGF-?). Here, we address this challenge in in vitro models of MB. METHODS:CB-derived NK cells were modified to express a dominant negative TGF-? receptor II (DNRII) using retroviral transduction. The ability of transduced CB cells to maintain function in the presence of medulloblastoma-conditioned media was then assessed. RESULTS:We observed that the cytotoxic ability of nontransduced CB-NK cells was reduced in the presence of TGF-?-rich, medulloblastoma-conditioned media (21.21?±?1.19% killing at E:T 5:1 in the absence vs. 14.98?±?2.11% in the presence of medulloblastoma-conditioned media, n?=?8, p?=?0.02), but was unaffected in CB-derived DNRII-transduced NK cells (21.11?±?1.84% killing at E:T 5:1 in the absence vs. 21.81?±?3.37 in the presence of medulloblastoma-conditioned media, n?=?8, p?=?0.85. We also observed decreased expression of CCR2 in untransduced NK cells (mean CCR2 MFI 826?±?117 in untransduced NK?+?MB supernatant from mean CCR2 MFI 1639.29?±?215 in no MB supernatant, n?=?7, p?=?0.0156), but not in the transduced cells. Finally, we observed that CB-derived DNRII-transduced NK cells may protect surrounding immune cells by providing a cytokine sink for TGF-? (decreased TGF-? levels of 610?±?265 pg/mL in CB-derived DNRII-transduced NK cells vs. 1817?±?342 pg/mL in untransduced cells; p?=?0.008). CONCLUSIONS:CB NK cells expressing a TGF-? DNRII may have a functional advantage over unmodified NK cells in the presence of TGF-?-rich MB, warranting further investigation on its potential applications for patients with medulloblastoma.

SUBMITTER: Powell AB

PROVIDER: S-EPMC6757414 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Medulloblastoma rendered susceptible to NK-cell attack by TGFβ neutralization.

Powell Allison B AB Yadavilli Sridevi S Saunders Devin D Van Pelt Stacey S Chorvinsky Elizabeth E Burga Rachel A RA Albihani Shuroug S Hanley Patrick J PJ Xu Zhenhua Z Pei Yanxin Y Yvon Eric S ES Hwang Eugene I EI Bollard Catherine M CM Nazarian Javad J Cruz Conrad Russell Y CRY

Journal of translational medicine 20190923 1

<h4>Background</h4>Medulloblastoma (MB), the most common pediatric brain cancer, presents with a poor prognosis in a subset of patients with high risk disease, or at recurrence, where current therapies are ineffective. Cord blood (CB) natural killer (NK) cells may be promising off-the-shelf effector cells for immunotherapy due to their recognition of malignant cells without the need for a known target, ready availability from multiple banks, and their potential to expand exponentially. However, ...[more]

PMID: 31547819

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Project description:Natural killer (NK) cells are lymphocytes of the innate immune system capable of killing hazardous cells, including virally infected cells. NK cell-mediated killing is triggered by activating receptors. Prominent among these is the activating receptor NKG2D, which binds several stress-induced ligands, among them major histocompatibility complex (MHC) class I-related chain A (MICA). Most of the human population is persistently infected with human cytomegalovirus (HCMV), a virus which employs multiple immune evasion mechanisms, many of which target NK cell responses. HCMV infection is mostly asymptomatic, but in congenitally infected neonates and in immunosuppressed patients it can lead to serious complications and mortality. Here we discovered that an HCMV protein named UL148A whose role was hitherto unknown is required for evasion of NK cells. We demonstrate that UL148A-deficient HCMV strains are impaired in their ability to downregulate MICA expression. We further show that when expressed by itself, UL148A is not sufficient for MICA targeting, but rather acts in concert with an unknown viral factor. Using inhibitors of different cellular degradation pathways, we show that UL148A targets MICA for lysosomal degradation. Finally, we show that UL148A-mediated MICA downregulation hampers NK cell-mediated killing of HCMV-infected cells. Discovering the full repertoire of HCMV immune evasion mechanisms will lead to a better understanding of the ability of HCMV to persist in the host and may also promote the development of new vaccines and drugs against HCMV.IMPORTANCE Human cytomegalovirus (HCMV) is a ubiquitous pathogen which is usually asymptomatic but that can cause serious complications and mortality in congenital infections and in immunosuppressed patients. One of the difficulties in developing novel vaccines and treatments for HCMV is its remarkable ability to evade our immune system. In particular, HCMV directs significant efforts to thwarting cells of the innate immune system known as natural killer (NK) cells. These cells are crucial for successful control of HCMV infection, and yet our understanding of the mechanisms which HCMV utilizes to elude NK cells is partial at best. In the present study, we discovered that a protein encoded by HCMV which had no known function is important for preventing NK cells from killing HCMV-infected cells. This knowledge can be used in the future for designing more-efficient HCMV vaccines and for formulating novel therapies targeting this virus.

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Medulloblastoma rendered susceptible to NK-cell attack by TGF? neutralization.

Publications

Medulloblastoma rendered susceptible to NK-cell attack by TGFβ neutralization.

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