Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on <i>BRAF</i>V600E Melanoma Lines with Vemurafenib

Frazao, Alexandra; Colombo, Marina; Fourmentraux-Neves, Emmanuelle; Messaoudene, Meriem; Rusakiewicz, Sylvie; Zitvogel, Laurence; Vivier, Éric; Vély, Frederic; Faure, Florence; Dréno, Brigitte; Benlalam, Houssem; Bouquet, Fanny; Savina, Ariel; Pasmant, Éric; Toubert, Antoine; Avril, Marie Françoise; Caignard, Anne

doi:10.1158/2326-6066.cir-16-0380

Cited by 18 publications

(24 citation statements)

References 48 publications

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“…Indeed, even though no evidence is reported so far in cancer cells, CO plays a pivotal role in reducing immune cell functions. 21 It is important to note that B7H6 and ULBP3 are expressed on MeOV-1 cells (up to 30 and 80% of positive cells, respectively), while ULBP1 and ULBP2 are not detectable. 20 They also showed that melanoma cell exposure to histone deacetylase inhibitors, known for their ability to increase the expression of ligands for NK activator receptors, 40 restored NK-mediated killing.…”

Section: Discussionmentioning

confidence: 95%

“…Both IL-15-activated NK cells (Figs. 21 However, the NK-mediated lysis of PLX4032-treated MeOV-1 cells did not increase upon mAb-mediated masking of HLA class I molecules with a specific mAb of IgM isotype (data not shown), thus suggesting that the reduction in NK cell lysis of BRAFi-treated MeOV-1 cells could rather reflect a decreased expression of ligands of activating NK receptors. 5c and 5d) were used as effectors.…”

Section: Ho-1 Silencing Restores the Ability Of Nk Cells To Degranulamentioning

confidence: 86%

“…It is conceivable that an important mediator of the immunomodulatory effect of HO-1 is CO. 21 Indeed, they showed an upregulatory trend of B7H6 expression paralleled by a reduction of ULBP2 expression and HLA class I molecules, resulting overall in a reduced NK cell-mediated killing. 39 In agreement with our data, other groups have recently shown a decreased NK cell activity toward melanoma cells treated with BRAFis.…”

Section: Discussionmentioning

confidence: 97%

“…39 In agreement with our data, other groups have recently shown a decreased NK cell activity toward melanoma cells treated with BRAFis. 21 The molecular pathways involved in the expression of B7H6 and ULBP3 are still poorly understood. 20 Other studies report an impaired NK cell activity in response to PLX4032-treated melanoma cells, due to a shifting of the balance between the expression of activating and inhibitory NK ligands.…”

Section: Discussionmentioning

confidence: 99%

“…20,21 Along this line, we analyzed cytokine-activated NK cells for their ability to undergo degranulation in the presence of MeOV-1 melanoma cell line either untreated (DMSO) or treated with PLX4032 (1 μM) for 24 hr. 20,21 Along this line, we analyzed cytokine-activated NK cells for their ability to undergo degranulation in the presence of MeOV-1 melanoma cell line either untreated (DMSO) or treated with PLX4032 (1 μM) for 24 hr.…”

Section: Ho-1 Silencing Restores the Ability Of Nk Cells To Degranulamentioning

confidence: 99%

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HO‐1 downregulation favors BRAF^V600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition

Furfaro

Ottonello

Loi

et al. 2019

Intl Journal of Cancer

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Heme oxygenase 1 (HO‐1) plays a pivotal role in preventing cell damage. Indeed, through the antioxidant, antiapoptotic and anti‐inflammatory properties of its metabolic products, it favors cell adaptation against different stressors. However, HO‐1 induction has also been related to the gain of resistance to therapy in different types of cancers and its involvement in cancer immune‐escape has been hypothesized. We have investigated the role of HO‐1 expression in Vemurafenib‐treated BRAFV600 melanoma cells in modulating their susceptibility to NK cell‐mediated recognition. Different cell lines, isolated in house from melanoma patients, have been exposed to 1–10 μM PLX4032, which efficiently reduced ERK phosphorylation. In three lines, Vemurafenib was able to induce only a limited decrease in cell viability, while HO‐1 expression was upregulated. HO‐1 silencing/inhibition was able to induce a further significant reduction of Vemurafenib‐treated melanoma viability. Moreover, while NK cell degranulation and killing activity were decreased upon interaction with melanoma exposed to Vemurafenib, HO‐1 silencing was able to completely restore NK cell ability to degranulate and kill. Furthermore, melanoma cell treatment with Vemurafenib downregulated the expression of ligands of NKp30 and NKG2D activating receptors, and HO‐1 silencing/inhibition was able to restore their expression. Our results indicate that HO‐1 downregulation can both improve the efficacy of Vemurafenib on melanoma cells and favor melanoma susceptibility to NK cell‐mediated recognition and killing.

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Section: Discussionmentioning

confidence: 95%

Section: Ho-1 Silencing Restores the Ability Of Nk Cells To Degranulamentioning

confidence: 86%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Ho-1 Silencing Restores the Ability Of Nk Cells To Degranulamentioning

confidence: 99%

See 3 more Smart Citations

HO‐1 downregulation favors BRAF^V600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition

Furfaro

Ottonello

Loi

et al. 2019

Intl Journal of Cancer

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Rationale for Immune Checkpoint Inhibitors Plus Targeted Therapy in Metastatic Melanoma

et al. 2020

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In recent years, the management of metastatic melanoma has been transformed by the emergence of immune checkpoint inhibitors and targeted therapies that significantly improve patient survival. The complementary response kinetics of these treatment approaches, supported by mechanistic evidence that targeted therapy affects immune aspects of the tumor microenvironment, suggest that the optimal combination or sequencing of immune checkpoint inhibitors and targeted therapy may provide additional clinical benefit.OBSERVATIONS Clinical responses to BRAF and/or MEK inhibitors are associated with immune changes within the tumor microenvironment that have the potential to increase the sensitivity of BRAF V600-mutant melanoma to immune checkpoint inhibitors. The combination of immune checkpoint inhibitors with targeted therapy may therefore increase duration of response, improve tumor control, extend survival, and increase the proportion of patients experiencing durable benefit. A targeted therapy-immune checkpoint inhibitor sequencing approach may also be supported by this evidence, but clinical questions regarding optimal timing, duration, and patient selection remain. CONCLUSIONS AND RELEVANCEThis review outlines the rationale and preclinical evidence that support immune checkpoint inhibitor plus targeted therapy combination and sequencing strategies in melanoma and highlights the results available to date from clinical trials exploring these approaches to treatment. Several late-stage trials are under way looking to answer open questions in this field and address the continuing debate surrounding up-front combination vs sequencing. As phase 3 data have begun to emerge, trial designs and available data from key studies are discussed in the context of their resultant implications for clinical practice.

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Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by Anticancer Therapies in the Era of Checkpoint Inhibitors

et al. 2022

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IMPORTANCEAlthough typically impressive, objective responses to immune checkpoint inhibitors (ICIs) occur in only 12.5% of patients with advanced cancer. The majority of patients do not respond due to cell-intrinsic resistance mechanisms, including human leukocyte antigen (HLA) class I antigen-processing machinery (APM) defects. The APM defects, which have a negative effect on neoantigen presentation to cytotoxic T lymphocytes (CTLs), are present in the majority of malignant tumors. These defects are caused by gene variations in less than 25% of cases and by dysregulated signaling and/or epigenetic changes in most of the remaining cases, making them frequently correctable. This narrative review summarizes the growing clinical evidence that chemotherapy, targeted therapies, and, to a lesser extent, radiotherapy can correct HLA class I APM defects in cancer cells and improve responses to ICIs.OBSERVATIONS Most chemotherapeutics enhance HLA class I APM component expression and function in cancer cells, tumor CTL infiltration, and responses to ICIs in preclinical and clinical models. Despite preclinical evidence, radiotherapy does not appear to upregulate HLA class I expression in patients and does not enhance the efficacy of ICIs in clinical settings. The latter findings underscore the need to optimize the dose and schedule of radiation and timing of ICI administration to maximize their immunogenic synergy. By increasing DNA and chromatin accessibility, epigenetic agents (histone deacetylase inhibitors, DNA methyltransferase inhibitors, and EZH2 inhibitors) enhance HLA class I APM component expression and function in many cancer types, a crucial contributor to their synergy with ICIs in patients. Furthermore, epidermal growth factor receptor (EGFR) inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors are effective at upregulating HLA class I expression in EGFR-and BRAF-variant tumors, respectively; these changes may contribute to the clinical responses induced by these inhibitors in combination with ICIs.CONCLUSIONS AND RELEVANCE This narrative review summarizes evidence indicating that chemotherapy and targeted therapies are effective at enhancing HLA class I APM component expression and function in cancer cells. The resulting increased immunogenicity and recognition and elimination of cancer cells by cognate CTLs contributes to the antitumor activity of these therapies as well as to their synergy with ICIs.

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Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib

Cited by 18 publications

References 48 publications

HO‐1 downregulation favors BRAF^V600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition

HO‐1 downregulation favors BRAF^V600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition

Rationale for Immune Checkpoint Inhibitors Plus Targeted Therapy in Metastatic Melanoma

Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by Anticancer Therapies in the Era of Checkpoint Inhibitors

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Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib

Cited by 18 publications

References 48 publications

HO‐1 downregulation favors BRAFV600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition

HO‐1 downregulation favors BRAFV600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition

Rationale for Immune Checkpoint Inhibitors Plus Targeted Therapy in Metastatic Melanoma

Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by Anticancer Therapies in the Era of Checkpoint Inhibitors

Contact Info

Product

Resources

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HO‐1 downregulation favors BRAF^V600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition

HO‐1 downregulation favors BRAF^V600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition