Expression of immune checkpoint PD‑1 in non‑small cell lung cancer is associated with tumor cell DNA‑dependent protein kinase

Saar, M.; Narits, Jaanika; Mägi, Laura; Aaspõllu, Hardi; Vapper, Annett; Kase, Marju; Minajeva, Ave; Vooder, Tõnu; Tamm, Hannes; Buldakov, Maksim; Lavõgina, Darja; Jaal, Jana

doi:10.3892/mco.2021.2369

Cited by 6 publications

(7 citation statements)

References 47 publications

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“…However, all the mechanisms underlying synergistic interactions in immunotherapy and chemotherapy combinations are not completely understood and described. We have demonstrated earlier a significant positive correlation between the PD-1/PD-L1 axis and tumour cell enzyme DNA-PK, which is part of a key pathway involved in the repair of cytotoxic cancer therapy induced damage (15). Therefore, to confirm our hypothesis about an alternative role of ICIs in addition to immune activation, we performed the study to test whether ICIs can affect the cytotoxicity of chemotherapeutics.…”

Section: Discussionmentioning

confidence: 86%

“…In a previous study we demonstrated a significant positive correlation between the PD-1/PD-L1 axis and tumour cell enzyme DNA-dependent protein kinase (DNA-PK), which is part of a key pathway involved in the repair of cytotoxic cancer therapy-induced damage (15). Therefore, this study aims to explore whether ICIs can affect the cytotoxicity of chemotherapeutics in clinically relevant lung adenocarcinoma cell lines with different PD-L1 expression levels (high: HCC-44, low: A-549) thus specifically addressing the tumour-cell centred effects of combined therapies.…”

Section: Immune Checkpoint Inhibitors Modulate the Cytotoxic Effect O...mentioning

confidence: 99%

“…The immunohistochemistry (IHC) with PFA-fixed cell pellets and the following light microscopy were carried out according to the previously published protocols (15); 22C3 pharmDx primary antibody was used for staining. The bright-field imaging of IHC samples was carried out using light microscopy by the Pathology Department of Tartu University Hospital according to the protocols used for the analysis of clinical samples (accreditation certificate No M017 by the Estonian Accreditation Centre).…”

Section: Chemicals and Equipmentmentioning

confidence: 99%

“…Second, motivated by the previously reported positive correlation between the PD-1/PD-L1 axis and tumour cell DNA-PK expression (15), we examined whether the potentiating effects of ICIs can occur via augmentation of the chemotherapy-induced DNA damage. For that, we carried out immunostaining of a well-recognized DNA damage marker γH2AX in both the HCC-44 and A549 cell lines after 48-h Table I.…”

Section: Effects Of Chemotherapeutic Agents and Mixtures With Icismentioning

confidence: 99%

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Immune checkpoint inhibitors modulate the cytotoxic effect of chemotherapy in lung adenocarcinoma cells

et al. 2023

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Immunotherapy using immune checkpoint inhibitors (ICIs) has significantly improved survival in patients with non-small cell lung cancer (NSCLC), and ICIs are increasingly used in combination with cytotoxic treatments, such as chemotherapy. Although combined treatments are more effective, not all patients respond to the therapy; therefore, a detailed understanding of the effect of treatment combinations at the tumour level is needed. The present study aimed to explore whether ICIs could affect the cytotoxic effects of chemotherapy on lung adenocarcinoma cell lines with different PD-L1 expression levels (high, HCC-44; low, A-549). Using the resazurin-based assay, the efficacy of seven chemotherapeutic agents (cisplatin, etoposide, gemcitabine, pemetrexed, vinorelbine, docetaxel and paclitaxel) was compared in the presence or absence of the individually chosen single doses of four ICIs (nivolumab, pembrolizumab, atezolizumab and durvalumab). The results revealed that different ICIs can exhibit either potentiating or depotentiating effects, depending on the chemotherapy agent or lung adenocarcinoma cell line used. Durvalumab was the most promising ICI, which potentiated most chemotherapy agents in both cell lines, especially in the case of high PD-L1 expression. By contrast, nivolumab, exhibited depotentiating trends in several combinations. The immunostaining of γH2AX in treated cells confirmed that the potentiation of the chemotherapeutic cytotoxicity by durvalumab was at least partially mediated via increased DNA damage; however, this effect was strongly dependent on the chemotherapy agent and cell line used. Our future studies aim to address the specific mechanisms underlying the observed ICI-induced potentiation or depotentiation.

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Section: Discussionmentioning

confidence: 86%

Section: Immune Checkpoint Inhibitors Modulate the Cytotoxic Effect O...mentioning

confidence: 99%

Section: Chemicals and Equipmentmentioning

confidence: 99%

Section: Effects Of Chemotherapeutic Agents and Mixtures With Icismentioning

confidence: 99%

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Immune checkpoint inhibitors modulate the cytotoxic effect of chemotherapy in lung adenocarcinoma cells

et al. 2023

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“…Recent studies have found that the PD-1 expression is up-regulated in lung cancer, gastric cancer, hepatocellular carcinoma, multiple myeloma, breast cancer, renal cell carcinoma and melanoma [22][23][24][25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Clinical Implications of Aberrant PD-1 Expression for Acute Leukemia Prognosis

Ruan

Wang

Zhang

et al. 2022

Preprint

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Background: Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the most common types of leukemia in adults with an overall poor prognosis. PD-1 alone or combined with other immune checkpoint blockade is a promising research direction for the treatment of acute leukemia (AL) patients. However, clinical Implications of aberrant PD-1 expression in peripheral CD4+ and CD8+ T lymphocytes of AML and ALL patients in assessing the prognosis of diseases, remains inconclusive. Methods: In the present study, we used flow cytometry to evaluate PD-1 expression on the surface of CD4+ and CD8+ T lymphocytes in the peripheral circulation of AML and ALL patients and its clinical significance. A total of 53 AML patients, 44 ALL patients and 28 healthy controls were enrolled in this study and peripheral blood specimens were detected by flow cytometry. Results: Our results indicated that percentages of CD4+PD1+ and CD8+PD1+ T lymphocytes in newly diagnosed and non-remission groups were significantly higher than healthy control both in AML and ALL patients. The high level of CD4+PD1+ and CD8+PD1+ T lymphocyteswere respectively poor prognostic indicators of AML patients and ALL patients but had no significant correlation with most common clinical risks. Conclusions: Our findings show that aberrant PD-1 expression correlates with the prognosis of AL patient and may thus serve as poor prognostic indicators. Immunotherapy using PD-1 inhibitors may be a promising strategy for AML and ALL patients with peripheral circulating CD4+PD1+ and CD8+PD1+ T lymphocytes positively expressed, respectively.

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Clinical implications of aberrant PD-1 expression for acute leukemia prognosis

Ruan,

Wang,

Zhang

et al. 2023

Eur J Med Res

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Background Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the most common types of leukemia in adults with an overall poor prognosis. PD-1 alone or combined with other immune checkpoint blockade is a promising research direction for the treatment of acute leukemia (AL) patients. However, clinical Implications of aberrant PD-1 expression in peripheral CD4+ and CD8+ T lymphocytes of AML and ALL patients in assessing the prognosis of diseases, remains inconclusive. Methods In the present study, we used flow cytometry to evaluate PD-1 expression on the surface of CD4+ and CD8+ T lymphocytes in the peripheral circulation of AML and ALL patients and its clinical significance. A total of 53 AML patients, 44 ALL patients and 28 healthy controls were enrolled in this study and peripheral blood specimens were detected by flow cytometry. Results Our results indicated that percentages of CD4+ PD1+ and CD8+ PD1+ T lymphocytes in newly diagnosed and non-remission groups were significantly higher than healthy control both in AML and ALL patients. The high level of CD4+ PD1+ and CD8+ PD1+ T lymphocytes were respectively poor prognostic indicators of AML patients and ALL patients but had no significant correlation with most common clinical risks. Conclusions Our findings show that aberrant PD-1 expression correlates with the prognosis of AL patient and may thus serve as poor prognostic indicators. Immunotherapy using PD-1 inhibitors may be a promising strategy for AML and ALL patients with peripheral circulating CD4+ PD1+ and CD8+ PD1+ T lymphocytes positively expressed, respectively.

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Expression of immune checkpoint PD‑1 in non‑small cell lung cancer is associated with tumor cell DNA‑dependent protein kinase

Cited by 6 publications

References 47 publications

Immune checkpoint inhibitors modulate the cytotoxic effect of chemotherapy in lung adenocarcinoma cells

Immune checkpoint inhibitors modulate the cytotoxic effect of chemotherapy in lung adenocarcinoma cells

Clinical Implications of Aberrant PD-1 Expression for Acute Leukemia Prognosis

Clinical implications of aberrant PD-1 expression for acute leukemia prognosis

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