Aspirin‐targeted <scp>PD‐L1</scp> in lung cancer growth inhibition

Zhang, Yixiang; Lv, Changsheng; Dong, Yan; Yang, Qingkai

doi:10.1111/1759-7714.13433

Cited by 16 publications

(18 citation statements)

References 24 publications

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“…As was noted before, in vitro studies suggested a synergic effect of adding NSAID/ASA to PD-1/ PD-L1 inhibitors for a better anti-cancer effect [5][6][7]. More specifically, researchers found that ASA suppressed the growth of cancer cells, including lung cancer cells, via inhibiting PDL-1 overexpression [14][15]. Those findings could explain our suggested clinical benefit of using ASA in NSCLC patients at biochemical and histological levels, especially with PD-L1 inhibitors.…”

Section: Variablessupporting

confidence: 67%

Does the Combined Use of Aspirin and Immunotherapy Result in Better Outcomes in Non-Small Cell Lung Cancer Than Immunotherapy Alone?

Aiad¹,

Tahir²,

Fresco³

et al. 2022

Cureus

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Introduction: Immunotherapy works by stimulating the immune system against cancer cells. Resistance to immunotherapy represents a significant challenge in the field of medical oncology. The mechanisms by which cancer cells evade immunotherapy are not well understood. Prior research suggested overexpression of prostaglandin E-2 (PGE-2) by cancer cells, which bind to EP-2 and EP-4 receptors on the tumor-specific cytotoxic T-lymphocytes (CTLs) and suppress their anticancer role. This immunosuppressive effect is involved in evading the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade of immunotherapy, which fuels cancer cell growth and recurrence. Studies found that combining PGE-2 blockade and a PD-1 signaling inhibitor helped promote the anticancer immunity cells. If confirmed in a clinical setting, the above in vitro findings could be of great clinical significance.Methods: Given that aspirin (ASA) blocks PGE-2 production, this work aimed to evaluate whether ASA use with immunotherapy results in better outcomes than immunotherapy alone. We performed a retrospective chart review of 500 non-small cell lung cancer (NSCLC) patients aged 21 years or older treated with PD-1 and/or PD-L1 directed immunotherapy at St. Luke's University Health Network between July 2015 and July 2021. Relevant patient, disease, and treatment-related variables were collected, including ASA use (≥ 81 mg daily) and the type of immunotherapy. Bivariate analyses were conducted to determine which variables to include in a multivariable model.The four primary outcomes included survival at 18-months, both after diagnosis and starting immunotherapy, achieving complete remission (CR), and having a progressive disease (PD), as defined by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Secondary outcomes included therapyrelated toxicities and complications in the different treatment groups.Results: After bivariate analysis, no statistical significance was found for a difference in 18-month survival between ASA and non-ASA groups (50.3% vs 49.7%, p-value = 0.79). ASA with PD-L1 inhibitor showed a trend towards a higher likelihood of achieving CR [adjusted odds ratio (AOR) 1.85] with a p-value close to statistical significance (0.06). However, ASA with PD-L1 showed high statistical significance as an independent variable associated with a decreased likelihood of having PD (AOR 0.44, p < 0.001). These findings suggest that NSCLC patients receiving PD-L1 inhibitors could benefit more from daily ASA than patients treated with PD-1 inhibitors. Our study emphasizes using the Eastern Cooperative Oncology Group (ECOG) scoring of the performance status (PS) in NSCLC patients. Poorer PSwas associated with lower survival, decreased likelihood of CR, and more PD. Other variables associated with worse outcomes were advanced cancer stage at diagnosis and male gender. Low-PD-L1 expression in NSCLC was associated with an increased likelihood of survival; this could be of clinical significance, especially with previous studies su...

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Section: Variablessupporting

confidence: 67%

Does the Combined Use of Aspirin and Immunotherapy Result in Better Outcomes in Non-Small Cell Lung Cancer Than Immunotherapy Alone?

Aiad¹,

Tahir²,

Fresco³

et al. 2022

Cureus

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“…Aspirin suppresses platelet-associated invasion of OC cells [ 20 ]. Moreover, a recent study reports that aspirin inhibits lung cancer cell growth by regulating the TAZ/PD-L1 signaling [ 21 ], presenting the effect of aspirin on PD-L1 in lung cancer. Our data indicated that treatment with aspirin suppressed the OC cell proliferation in vitro .…”

Section: Discussionmentioning

confidence: 99%

Aspirin Suppressed PD-L1 Expression through Suppressing KAT5 and Subsequently Inhibited PD-1 and PD-L1 Signaling to Attenuate OC Development

Xiao

Zeng

et al. 2022

Journal of Oncology

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Ovarian cancer (OC) is a frequently occurred malignancy with high incidence and poor survival worldwide. In recent years, immune checkpoint inhibition that targets PD-1/PD-L1 axis has become an efficient and popular therapy for cancers. Aspirin (ASP), an anti-inflammatory drug, exhibits a wide spectrum of biological functions including anticancer property. However, the role of ASP treatment in ovarian cancer treatment remains unclear. In this work, we explored the role of ASP in modulating PD-L1 signaling during OC development. Notably, in vitro experiments showed that ASP treatment caused repressed proliferation of OC cells. The results from in vivo xenograft model suggested suppressed tumor growth and tumor weight under ASP treatment. ASP treatment also caused downregulated PD-L1 and Ki-67 levels in mice tumors. Moreover, the IFN-γ-caused PD-L1 accumulation was inhibited by ASP treatment. The administration of ASP decreased the expression of PD-L1 of OC cells in a coculture system with activated T cell or unstimulated PBMCs, along with decreased expression of PD-1 by activated T cells. ASP reversed PD-L1 expression caused by coculture with activated T cells and abolished the suppressed T cells activation and proliferation. Analysis on molecular mechanisms revealed that KAT5 bonded to the promoter region of PD-L1 and upregulated its expression via enhancing histone H3 lysine 27 acetylation (H3K27ac), whereas ASP downregulated KAT5 expression and blocked this phenomenon. Moreover, ASP enhanced the effect of antiPD-L1 therapy in the in vivo tumor model. Hence, we proposed that ASP decreased expression of PD-L1 protein via inhibiting the epigenetic regulation by KAT5 and suppressed the PD-1/PD-L1 signaling to attenuate tumor growth. ASP may be a promising adjuvant in OC immunotherapy.

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“…In the same study, cell-based analyses also showed that increasing doses of aspirin reduced the cancer cell viability along with long-term clonogenesis while affecting caspase-3 activity minimally (Der et al 2020 ). Besides, Zhang et al ( 2020a , b ) showed that aspirin reduced the protein levels of programmed cell death-ligand 1 (PD-L1) which is expressed in tumor cells and displays an inhibitory role in antitumor immunity in A549 and H1299 human lung cancer cell lines. Further, the promoter of PD-L1 was cloned in a luciferase reporter pGL3-basic plasmid and aspirin was shown to reduce luciferase activity of pGL3-PD-L1.…”

Section: The Origin and Development Of Nsaids: A Journey To The Pastmentioning

confidence: 99%

Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention

Ozleyen

Yilmaz

Donmez

et al. 2022

J Cancer Res Clin Oncol

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Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently prescribed drug classes with wide therapeutic applications over the centuries. Starting from the use of salicylate-containing willow leaves to the recent rise and fall of highly selective cyclooxygenase-2 (COX-2) inhibitors and the latest dual-acting anti-inflammatory molecules, they have displayed a rapid and ongoing evolution. Despite the enormous advances in the last twenty years, investigators are still in search of the design and development of more potent and safer therapy against inflammatory conditions. This challenge has been increasingly attractive as the emergence of inflammation as a common seed and unifying mechanism for most chronic diseases. Indeed, this fact put the NSAIDs in the spotlight for repurposing against inflammation-related disorders. This review attempts to present a historical perspective on the evolution of NSAIDs, regarding their COX-dependent/independent mode of actions, structural and mechanism-based classifications, and adverse effects. Additionally, a systematic review of previous studies was carried out to show the current situation in drug repurposing, particularly in cancers associated with the GI tract such as gastric and colorectal carcinoma. In the case of non-GI-related cancers, preclinical studies elucidating the effects and modes of action were collected and summarized.

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Aspirin‐targeted PD‐L1 in lung cancer growth inhibition

Cited by 16 publications

References 24 publications

Does the Combined Use of Aspirin and Immunotherapy Result in Better Outcomes in Non-Small Cell Lung Cancer Than Immunotherapy Alone?

Does the Combined Use of Aspirin and Immunotherapy Result in Better Outcomes in Non-Small Cell Lung Cancer Than Immunotherapy Alone?

Aspirin Suppressed PD-L1 Expression through Suppressing KAT5 and Subsequently Inhibited PD-1 and PD-L1 Signaling to Attenuate OC Development

Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention

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