PD‐L1 expression by tumor cell lines: A predictive marker in melanoma

Knol, Anne-Chantal; Nguyen, Jean–Michel; Pandolfino, Marie‐Christine; Denis, Marc G.; Khammari, Amir; Dréno, Brigitte

doi:10.1111/exd.13526

Cited by 10 publications

(7 citation statements)

References 40 publications

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“…This in vivo observation can be reenacted by exposing tumor cells to IFN-ɣ, thereby leading to a marked increase of PD-L1 expression (Knol et al [62] and Fig. 3a).…”

Section: Discussionmentioning

confidence: 86%

IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression

Thiem

Hesbacher

Kneitz

et al. 2019

J Exp Clin Cancer Res

115

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Background Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma. Methods We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway. Results For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53L22Q,W23S, a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53L22Q,W23S in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression. Conclusions While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.

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“…This in vivo observation can be reenacted by exposing tumor cells to IFN-ɣ, thereby leading to a marked increase of PD-L1 expression (Knol et al [62] and Fig. 3a).…”

Section: Discussionmentioning

confidence: 86%

IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression

Thiem

Hesbacher

Kneitz

et al. 2019

J Exp Clin Cancer Res

115

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“…To investigate this hypothesis we used the model of co-culture of a melanoma cell-line and autologous TILs obtained from the same patient (6), with the addition of IDO inhibitor. The endpoints were the frequency of reactive autologous T cells among the TILs and the expression of molecules involved in the recognition of tumour antigens by T cells with and without IDO inhibitor.…”

Section: Methodsmentioning

confidence: 99%

“…Tryptophan deficiency inhibits the activity and proliferation of T cells (5). A recent paper (6) has shown that IDO1 expression in metastatic melanoma lymph nodes is associated with an increased risk of relapse and death. Thus, we hypothesize that the presence of IDO in the tumour microenvironment could inhibit the activity of TILs, and that adding an IDO inhibitor to the TILs could increase their cytotoxic activity against melanoma cells.…”

mentioning

confidence: 99%

Effect of Indoleamine 2,3 Dioxygenase Inhibitor on the Cytotoxic Activity of Tumour-infiltrating Lymphocytes

Naour

Knol²,

Pandolfino³

et al. 2019

Acta Derm Venerol

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“…One obstacle is defined by the insufficient migration of CAR‐T cells from the blood vessels to the tumor site, which is necessary for effective tumor eradication . Once entered, CAR‐T cells need to struggle through the unfavourable tumor microenvironment (TME) in order to induce a potent anti‐tumor immune response . Finally, the selection of the optimal target antigen is an important step, as T cells should be equipped with a CAR recognizing an antigen that is exclusively expressed on cancer cells rather than on healthy tissue to prevent on‐target/off‐tumor toxicities .…”

Section: Introductionmentioning

confidence: 99%

CAR‐T cell therapy in melanoma: A future success story?

Simon

Uslu

2018

Experimental Dermatology

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Chimeric antigen receptor (CAR)‐T cells are one of the impressive recent success stories of anti‐cancer immunotherapy. Especially in haematological malignancies, this treatment strategy has shown promising results leading to the recent approval of two CAR‐T cell constructs targeting CD19 in the United States and the European Union. After the huge success in haematological cancers, the next step will be the evaluation of its efficacy in different solid tumors, which is currently investigated in preclinical as well as clinical settings. A commonly examined tumor model in the context of immunotherapy is melanoma, since it is known for its immunogenic features. However, the first results of CAR‐T cell therapy in solid tumors did not reveal the same impressive outcomes that were observed in haematological malignancies, as engineered cells need to cope with several challenges. Obstacles include the lack of migration of CAR‐T cells from blood vessels to the tumor site as well as the immunosuppressive tumor microenvironment within solid tumors. Another hurdle is posed by the identification of an ideal target antigen to avoid on‐target/off‐tumor toxicities. Regarding immune escape mechanisms, which can be developed by tumor cells to bypass immune recognition, the observation of antigen loss should also be considered. This article gives an overview of the challenges displayed in CAR‐T cell therapy for the use in solid tumors and discusses different new strategies and approaches that deal with these problems in order to improve CAR‐T cell therapy, particularly for its use in melanoma.

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PD‐L1 expression by tumor cell lines: A predictive marker in melanoma

Cited by 10 publications

References 40 publications

IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression

IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression

Effect of Indoleamine 2,3 Dioxygenase Inhibitor on the Cytotoxic Activity of Tumour-infiltrating Lymphocytes

CAR‐T cell therapy in melanoma: A future success story?

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