Escape from NK cell tumor surveillance by NGFR-induced lipid remodeling in melanoma

Lehmann, Julia; Caduff, Nicole; Krzywińska, Ewelina; Stierli, Salome; Salas-Bastos, Adrián; Loos, Benjamin; Levesque, Mitchell P.; Dummer, Reinhard; Stockmann, Christian; Münz, Christian; Diener, Johanna; Sommer, Lukas

doi:10.1126/sciadv.adc8825

Cited by 5 publications

(4 citation statements)

References 87 publications

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“…Sanchez-Del-Campo et al demonstrated that the MITF low melanoma cell population can be reduced by NK cell-mediated killing, whereas MITF high cells can escape NK cell surveillance [60]. On the contrary, the most recently published study revealed that overexpression of NGFR in melanoma cells resulted in a reduction of NK cell infiltration into xenografts and NK cell-mediated melanoma cell killing [61]. The authors suggest that NGFR is a promising therapeutic target in melanoma and genetically engineered chimeric antigen receptor (CAR)-NGFR NK cells might be used against melanoma.…”

Section: Discussionmentioning

confidence: 99%

Trametinib-Resistant Melanoma Cells Displaying MITFhigh/NGFRlow/IL-8low Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge

Koziej

Kluszczyńska

Hartman

et al. 2023

IJMS

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Despite significant advances in targeted therapies against the hyperactivated BRAFV600/MEK pathway for patients with unresectable metastatic melanoma, acquired resistance remains an unsolved clinical problem. In this study, we focused on melanoma cells resistant to trametinib, an agent broadly used in combination therapies. Molecular and cellular changes were assessed during alternating periods of trametinib withdrawal and rechallenge in trametinib-resistant cell lines displaying either a differentiation phenotype (MITFhigh/NGFRlow) or neural crest stem-like dedifferentiation phenotype (NGFRhigh/MITFlow). Neither drug withdrawal nor drug rechallenge induced cell death, and instead of loss of fitness, trametinib-resistant melanoma cells adapted to altered conditions by phenotype switching. In resistant cells displaying a differentiation phenotype, trametinib withdrawal markedly decreased MITF level and activity, which was associated with reduced cell proliferation capacity, and induced stemness assessed as NGFR-positive cells and senescence features, including IL-8 expression and secretion. All these changes could be reversed by trametinib re-exposure, which emphasizes melanoma cell plasticity. Trametinib-resistant cells displaying a dedifferentiation phenotype were less responsive presumably due to the already low level of MITF, a master regulator of the melanoma phenotype. Considering new directions of the development of anti-melanoma treatment, our study suggests that the phenotype of melanomas resistant to targeted therapy might be a crucial determinant of the selection of second-line therapy for melanoma patients.

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Section: Discussionmentioning

confidence: 99%

Trametinib-Resistant Melanoma Cells Displaying MITFhigh/NGFRlow/IL-8low Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge

Koziej

Kluszczyńska

Hartman

et al. 2023

IJMS

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“…Other markers beyond MITF and AXL can give insight to melanoma phenotypes produced by EMT. For example, increased nerve growth factor receptor (NGFR) can mark a post-EMT state ( 25 ) associated with T cell resistance ( 14 ) and NK cell resistance, enhancing metastatic potential ( 110 ). EMT is a process at the cellular level, but also the tumoral level.…”

Section: Immune Escape and Epithelial-to-mesenchymal Transitionmentioning

confidence: 99%

Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy

Shirley,

Chhabra,

Amiri

et al. 2024

Front. Immunol.

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Melanoma is one of the most lethal neoplasms of the skin. Despite the revolutionary introduction of immune checkpoint inhibitors, metastatic spread, and recurrence remain critical problems in resistant cases. Melanoma employs a multitude of mechanisms to subvert the immune system and successfully metastasize to distant organs. Concerningly, recent research also shows that tumor cells can disseminate early during melanoma progression and enter dormant states, eventually leading to metastases at a future time. Immune escape and metastasis have previously been viewed as separate phenomena; however, accumulating evidence is breaking down this dichotomy. Recent research into the progressive mechanisms of melanoma provides evidence that dedifferentiation similar to classical epithelial to mesenchymal transition (EMT), genes involved in neural crest stem cell maintenance, and hypoxia/acidosis, are important factors simultaneously involved in immune escape and metastasis. The likeness between EMT and early dissemination, and differences, also become apparent in these contexts. Detailed knowledge of the mechanisms behind “dual drivers” simultaneously promoting metastatically inclined and immunosuppressive environments can yield novel strategies effective in disabling multiple facets of melanoma progression. Furthermore, understanding progression through these drivers may provide insight towards novel treatments capable of preventing recurrence arising from dormant dissemination or improving immunotherapy outcomes.

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“…Importantly, CD271 has been linked to immune escape in multiple reports. CD271 can be induced by IFNγ, which is produced in high volumes by NK cells, thus contributing to immune escape by driving the downregulation of melanoma antigens [250,251]. If future CAR-NK studies can be designed to secrete a synthetic peptide that can inhibit CD271, this may be able to restore endogenous effector cell recruitment for concerted tumor cell elimination alongside CAR-NK cells.…”

Section: Potential Targets For Car-nk Cell Therapies In Melanomamentioning

confidence: 99%

CAR NK Cell Therapy for the Treatment of Metastatic Melanoma: Potential & Prospects

Hibler,

Merlino,

2023

Cells

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Melanoma is among the most lethal forms of cancer, accounting for 80% of deaths despite comprising just 5% of skin cancer cases. Treatment options remain limited due to the genetic and epigenetic mechanisms associated with melanoma heterogeneity that underlie the rapid development of secondary drug resistance. For this reason, the development of novel treatments remains paramount to the improvement of patient outcomes. Although the advent of chimeric antigen receptor-expressing T (CAR-T) cell immunotherapies has led to many clinical successes for hematological malignancies, these treatments are limited in their utility by their immune-induced side effects and a high risk of systemic toxicities. CAR natural killer (CAR-NK) cell immunotherapies are a particularly promising alternative to CAR-T cell immunotherapies, as they offer a more favorable safety profile and have the capacity for fine-tuned cytotoxic activity. In this review, the discussion of the prospects and potential of CAR-NK cell immunotherapies touches upon the clinical contexts of melanoma, the immunobiology of NK cells, the immunosuppressive barriers preventing endogenous immune cells from eliminating tumors, and the structure and design of chimeric antigen receptors, then finishes with a series of proposed design innovations that could improve the efficacy CAR-NK cell immunotherapies in future studies.

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Escape from NK cell tumor surveillance by NGFR-induced lipid remodeling in melanoma

Cited by 5 publications

References 87 publications

Trametinib-Resistant Melanoma Cells Displaying MITFhigh/NGFRlow/IL-8low Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge

Trametinib-Resistant Melanoma Cells Displaying MITFhigh/NGFRlow/IL-8low Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge

Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy

CAR NK Cell Therapy for the Treatment of Metastatic Melanoma: Potential & Prospects

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