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

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

Publication date: Sep 11, 2019

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.

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.

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 p53, a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53 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.

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.

Thiem, A., Hesbacher, S., Kneitz, H., di Primio, T., Heppt, M.V., Hermanns, H.M., Goebeler, M., Meierjohann, S., Houben, R., and Schrama, D. IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression. 24067. 2019 J Exp Clin Cancer Res (38):1.

Concepts Keywords
Atlas Immunohistochemistry tumors TP53
Basal Evidence tumor
Cas9 Immunotherapy
CD274 Branches of biology
CRISPR Medicine
Ectopic Expression Cancer
Flow Cytometry Immune system
Frequency Tumor suppressor genes
Gene PD-L1
Genome Cancer treatments
IFN Gamma P53
IFNG Checkpoint inhibitor
Immunoblot Melanoma
Immunohistochemistry
Immunotherapy
JAK2
Knockout
Melanoma
MRNA
P53
Proteome
TP53
Tumor Suppressor
Wildtype

Semantics

Type Source Name
gene UNIPROT IMPACT
gene UNIPROT JAK2
disease DOID cancer
disease MESH cancer
drug DRUGBANK Tropicamide
gene UNIPROT RPL17
gene UNIPROT TP53
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
gene UNIPROT CD274
gene UNIPROT IFNG

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