PD-L1 is an immune checkpoint inhibitor, whose surface expression may be exploited by cancer cells to escape T cell-mediated immune recognition. PD-L1 expression and nuclear localization can be affected by epigenetic modifications, such as acetylation. In this study, we showed that VPA, a class I/IIa HDAC inhibitor, upregulated PD-L1 expression on the surface of pancreatic cancer cells. To this effect contributed the increased transcription, in correlation with histone acetylation of the PD-L1 gene and the acetylation of PD-L1 protein, which led to an increased interaction with TRAPPC4, molecule involved in PD-L1 recycling to the cell membrane. Interestingly, the BRD4 inhibitor JQ-1, counteracted PD-L1 transcription and reduced its surface expression, suggesting that such a combination could improve the outcome of VPA treatment, also because it increased the cytotoxic effect of VPA. Also considering that this HDACi did not upregulate PD-L2 and that the supernatant of VPA-treated cancer cells did not increase PD-L1 expression on the surface of macrophages exposed to it.

Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1 / Romeo, Maria Anele; Gilardini Montani, Maria Saveria; Santarelli, Roberta; Benedetti, Rossella; Arena, Andrea; Cirone, Mara. - In: DISCOVER ONCOLOGY. - ISSN 2730-6011. - 14:1(2023), p. 152. [10.1007/s12672-023-00766-4]

Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1

Romeo, Maria Anele;Gilardini Montani, Maria Saveria;Santarelli, Roberta;Benedetti, Rossella;Arena, Andrea;Cirone, Mara
2023

Abstract

PD-L1 is an immune checkpoint inhibitor, whose surface expression may be exploited by cancer cells to escape T cell-mediated immune recognition. PD-L1 expression and nuclear localization can be affected by epigenetic modifications, such as acetylation. In this study, we showed that VPA, a class I/IIa HDAC inhibitor, upregulated PD-L1 expression on the surface of pancreatic cancer cells. To this effect contributed the increased transcription, in correlation with histone acetylation of the PD-L1 gene and the acetylation of PD-L1 protein, which led to an increased interaction with TRAPPC4, molecule involved in PD-L1 recycling to the cell membrane. Interestingly, the BRD4 inhibitor JQ-1, counteracted PD-L1 transcription and reduced its surface expression, suggesting that such a combination could improve the outcome of VPA treatment, also because it increased the cytotoxic effect of VPA. Also considering that this HDACi did not upregulate PD-L2 and that the supernatant of VPA-treated cancer cells did not increase PD-L1 expression on the surface of macrophages exposed to it.
2023
Acetylation; Cytokines; HDACi; JQ-1; PD-L1; Pancreatic cancer; TRAPPC4; VPA
01 Pubblicazione su rivista::01a Articolo in rivista
Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1 / Romeo, Maria Anele; Gilardini Montani, Maria Saveria; Santarelli, Roberta; Benedetti, Rossella; Arena, Andrea; Cirone, Mara. - In: DISCOVER ONCOLOGY. - ISSN 2730-6011. - 14:1(2023), p. 152. [10.1007/s12672-023-00766-4]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1696294
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