Propranolol reduces IFN-γ driven PD-L1 immunosuppression and improves anti-tumour immunity in ovarian cancer

M Falcinelli; G Al-Hity; S Baron; M Mampay; M C Allen; M Samuels; W Jones; C Cilibrasi; Renee L Flaherty; G Giamas; P H Thaker; M S Flint

doi:10.1016/j.bbi.2023.02.011

Propranolol reduces IFN-γ driven PD-L1 immunosuppression and improves anti-tumour immunity in ovarian cancer

M Falcinelli, G Al-Hity, S Baron, M Mampay, M C Allen, M Samuels, W Jones, C Cilibrasi, Renee L Flaherty, G Giamas, P H Thaker, M S Flint

Research output: Contribution to journal › Article › peer-review

Abstract

The immune system plays an important role in controlling epithelial ovarian cancer (EOC). EOC is considered to be a "cold tumour," a tumour that has not triggered a strong response by the immune system. However, tumour infiltrating lymphocytes (TILs) and the expression of programmed cell death ligand (PD-L1) are used as prognostic indicators in EOC. Immunotherapy such as PD-(L)1 inhibitors have shown limited benefit in EOC. Since the immune system is affected by behavioural stress and the beta-adrenergic signalling pathway, this study aimed to explore the impact of propranolol (PRO), a beta-blocker, on anti-tumour immunity in both in vitro and in vivo EOC models. Noradrenaline (NA), an adrenergic agonist, did not directly regulate PD-L1 expression but PD-L1 was significantly upregulated by IFN-γ in EOC cell lines. IFN-γ also increased PD-L1 on extracellular vesicles (EVs) released by ID8 cells. PRO significantly decreased IFN-γ levels in primary immune cells activated ex vivo and showed increased viability of the CD8 cell population in an EV-immune cell co-incubation. In addition, PRO reverted PD-L1 upregulation and significantly decreased IL-10 levels in an immune-cancer cell co-culture. Chronic behavioural stress increased metastasis in mice while PRO monotherapy and the combo of PRO and PD-(L)1 inhibitor significantly decreased stress-induced metastasis. The combined therapy also reduced tumour weight compared to the cancer control group and induced anti-tumour T-cell responses with significant CD8 expression in tumour tissues. In conclusion, PRO showed a modulation of the cancer immune response by decreasing IFN-γ production and, in turn, IFN-γ-mediated PD-L1 overexpression. The combined therapy of PRO and PD-(L)1 inhibitor decreased metastasis and improved anti-tumour immunity offering a promising new therapy. [Abstract copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.]

Original language	English
Pages (from-to)	1-12
Number of pages	12
Journal	Brain Behavior and Immunity
Volume	110
DOIs	https://doi.org/10.1016/j.bbi.2023.02.011
Publication status	Published - 14 Feb 2023

Bibliographical note

Funding Information:
The authors would like to thank Dr Intabli and Mr Sinha for their technical support with PCR and flow cytometry and Dr Maher for technical support. We would also like to thank Professors Andrea Pepper and Chris Pepper for the use of their flow cytometer. This work was funded by a University of Brighton PhD scholarship.

Keywords

Ovarian cancer
PD-(L)1 inhibitor
Propranolol
Stress

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title = "Propranolol reduces IFN-γ driven PD-L1 immunosuppression and improves anti-tumour immunity in ovarian cancer",

abstract = "The immune system plays an important role in controlling epithelial ovarian cancer (EOC). EOC is considered to be a {"}cold tumour,{"} a tumour that has not triggered a strong response by the immune system. However, tumour infiltrating lymphocytes (TILs) and the expression of programmed cell death ligand (PD-L1) are used as prognostic indicators in EOC. Immunotherapy such as PD-(L)1 inhibitors have shown limited benefit in EOC. Since the immune system is affected by behavioural stress and the beta-adrenergic signalling pathway, this study aimed to explore the impact of propranolol (PRO), a beta-blocker, on anti-tumour immunity in both in vitro and in vivo EOC models. Noradrenaline (NA), an adrenergic agonist, did not directly regulate PD-L1 expression but PD-L1 was significantly upregulated by IFN-γ in EOC cell lines. IFN-γ also increased PD-L1 on extracellular vesicles (EVs) released by ID8 cells. PRO significantly decreased IFN-γ levels in primary immune cells activated ex vivo and showed increased viability of the CD8 cell population in an EV-immune cell co-incubation. In addition, PRO reverted PD-L1 upregulation and significantly decreased IL-10 levels in an immune-cancer cell co-culture. Chronic behavioural stress increased metastasis in mice while PRO monotherapy and the combo of PRO and PD-(L)1 inhibitor significantly decreased stress-induced metastasis. The combined therapy also reduced tumour weight compared to the cancer control group and induced anti-tumour T-cell responses with significant CD8 expression in tumour tissues. In conclusion, PRO showed a modulation of the cancer immune response by decreasing IFN-γ production and, in turn, IFN-γ-mediated PD-L1 overexpression. The combined therapy of PRO and PD-(L)1 inhibitor decreased metastasis and improved anti-tumour immunity offering a promising new therapy. [Abstract copyright: Copyright {\textcopyright} 2023 The Author(s). Published by Elsevier Inc. All rights reserved.]",

keywords = "Ovarian cancer, PD-(L)1 inhibitor, Propranolol, Stress",

author = "M Falcinelli and G Al-Hity and S Baron and M Mampay and Allen, {M C} and M Samuels and W Jones and C Cilibrasi and Flaherty, {Renee L} and G Giamas and Thaker, {P H} and Flint, {M S}",

note = "Funding Information: The authors would like to thank Dr Intabli and Mr Sinha for their technical support with PCR and flow cytometry and Dr Maher for technical support. We would also like to thank Professors Andrea Pepper and Chris Pepper for the use of their flow cytometer. This work was funded by a University of Brighton PhD scholarship.",

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AU - Falcinelli, M

AU - Al-Hity, G

AU - Baron, S

AU - Mampay, M

AU - Allen, M C

AU - Samuels, M

AU - Jones, W

AU - Cilibrasi, C

AU - Flaherty, Renee L

AU - Giamas, G

AU - Thaker, P H

AU - Flint, M S

N1 - Funding Information: The authors would like to thank Dr Intabli and Mr Sinha for their technical support with PCR and flow cytometry and Dr Maher for technical support. We would also like to thank Professors Andrea Pepper and Chris Pepper for the use of their flow cytometer. This work was funded by a University of Brighton PhD scholarship.

PY - 2023/2/14

Y1 - 2023/2/14

N2 - The immune system plays an important role in controlling epithelial ovarian cancer (EOC). EOC is considered to be a "cold tumour," a tumour that has not triggered a strong response by the immune system. However, tumour infiltrating lymphocytes (TILs) and the expression of programmed cell death ligand (PD-L1) are used as prognostic indicators in EOC. Immunotherapy such as PD-(L)1 inhibitors have shown limited benefit in EOC. Since the immune system is affected by behavioural stress and the beta-adrenergic signalling pathway, this study aimed to explore the impact of propranolol (PRO), a beta-blocker, on anti-tumour immunity in both in vitro and in vivo EOC models. Noradrenaline (NA), an adrenergic agonist, did not directly regulate PD-L1 expression but PD-L1 was significantly upregulated by IFN-γ in EOC cell lines. IFN-γ also increased PD-L1 on extracellular vesicles (EVs) released by ID8 cells. PRO significantly decreased IFN-γ levels in primary immune cells activated ex vivo and showed increased viability of the CD8 cell population in an EV-immune cell co-incubation. In addition, PRO reverted PD-L1 upregulation and significantly decreased IL-10 levels in an immune-cancer cell co-culture. Chronic behavioural stress increased metastasis in mice while PRO monotherapy and the combo of PRO and PD-(L)1 inhibitor significantly decreased stress-induced metastasis. The combined therapy also reduced tumour weight compared to the cancer control group and induced anti-tumour T-cell responses with significant CD8 expression in tumour tissues. In conclusion, PRO showed a modulation of the cancer immune response by decreasing IFN-γ production and, in turn, IFN-γ-mediated PD-L1 overexpression. The combined therapy of PRO and PD-(L)1 inhibitor decreased metastasis and improved anti-tumour immunity offering a promising new therapy. [Abstract copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.]

AB - The immune system plays an important role in controlling epithelial ovarian cancer (EOC). EOC is considered to be a "cold tumour," a tumour that has not triggered a strong response by the immune system. However, tumour infiltrating lymphocytes (TILs) and the expression of programmed cell death ligand (PD-L1) are used as prognostic indicators in EOC. Immunotherapy such as PD-(L)1 inhibitors have shown limited benefit in EOC. Since the immune system is affected by behavioural stress and the beta-adrenergic signalling pathway, this study aimed to explore the impact of propranolol (PRO), a beta-blocker, on anti-tumour immunity in both in vitro and in vivo EOC models. Noradrenaline (NA), an adrenergic agonist, did not directly regulate PD-L1 expression but PD-L1 was significantly upregulated by IFN-γ in EOC cell lines. IFN-γ also increased PD-L1 on extracellular vesicles (EVs) released by ID8 cells. PRO significantly decreased IFN-γ levels in primary immune cells activated ex vivo and showed increased viability of the CD8 cell population in an EV-immune cell co-incubation. In addition, PRO reverted PD-L1 upregulation and significantly decreased IL-10 levels in an immune-cancer cell co-culture. Chronic behavioural stress increased metastasis in mice while PRO monotherapy and the combo of PRO and PD-(L)1 inhibitor significantly decreased stress-induced metastasis. The combined therapy also reduced tumour weight compared to the cancer control group and induced anti-tumour T-cell responses with significant CD8 expression in tumour tissues. In conclusion, PRO showed a modulation of the cancer immune response by decreasing IFN-γ production and, in turn, IFN-γ-mediated PD-L1 overexpression. The combined therapy of PRO and PD-(L)1 inhibitor decreased metastasis and improved anti-tumour immunity offering a promising new therapy. [Abstract copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.]

KW - Ovarian cancer

KW - PD-(L)1 inhibitor

KW - Propranolol

KW - Stress

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DO - 10.1016/j.bbi.2023.02.011

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SN - 0889-1591

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SP - 1

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JO - Brain Behavior and Immunity

JF - Brain Behavior and Immunity

ER -

Propranolol reduces IFN-γ driven PD-L1 immunosuppression and improves anti-tumour immunity in ovarian cancer

Abstract

Bibliographical note

Keywords

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