Control of PD-L1 Expression by Oncogenic Activation of the AKT–mTOR Pathway in Non–Small Cell Lung Cancer

Lastwika, Kristin J.; Wilson, Willie; Li, Qing Kay; Norris, Jeffrey W.; Xu, Huimin; Ghazarian, Sharon R.; Kitagawa, Hiroshi; Kawabata, Shigeru; Taube, Janis M.; Yao, Sheng; Liu, Linda N.; Gills, Joell J.; Dennis, Phillip A.

doi:10.1158/0008-5472.can-14-3362

Cited by 602 publications

(491 citation statements)

References 53 publications

(56 reference statements)

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“…They saw that the redistribution of PD-L1 from the cell surface to the nucleus was associated with a translocation of phosphorylated Akt from the membrane to the nucleus. They also reported that inhibition of Akt partially decreased PD-L1 expression on the surface, findings that are supported by Latswika et al 35 Further research on the effect of chemotherapeutics on Akt signaling is warranted in order to fully unravel the underlying mechanisms that might be responsible for PD-L1 downregulation. Compared to the unpretreated, fewer pretreated patients had TIM-3 C TILs in their stroma, which is in line with findings from Zhang et al in diffuse large B-cell lymphoma.…”

Section: Discussionmentioning

confidence: 64%

“…33,34 Expression of PD-L1 on the cell surface has been associated with the activation of the PI3K/Akt signaling pathway and PD-L1 has been described to be a downstream target of Akt. 35 Ghebeh et al 34 reported a significant downregulation of PD-L1 on the surface of breast cancer cell lines after doxorubicin treatment which was accompanied by an upregulation of PD-L1 in the nucleus. They saw that the redistribution of PD-L1 from the cell surface to the nucleus was associated with a translocation of phosphorylated Akt from the membrane to the nucleus.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

et al. 2016

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Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and an increasing incidence, for which novel therapeutic strategies are urgently required. Since the immune system has been described to play a presumed role in the protection against MPM, characterization of its tumor immune microenvironment (TME) and immune checkpoints can identify new immunotherapeutic targets and their predictive and/or prognostic value.To characterize the TME and the immune checkpoint expression profile, we performed immunohistochemistry (IHC) on formalin-fixed paraffin embedded (FFPE) tissue sections from 54 MPM patients (40 at time of diagnosis; 14 treated with chemotherapy). We stained for PD-1, PD-L1, TIM-3, LAG-3, CD4, CD8, CD45RO, granzyme B, FoxP3 and CD68. Furthermore, we analyzed the relationship between the immunological parameters and survival, as well as response to chemotherapy. We found that TIM-3, PD-1 and PD-L1 were expressed on both immune and tumor cells. Strikingly, PD-1 and PD-L1 expression on tumor cells was only seen in unpretreated samples. No LAG-3 expression was observed. CD45RO expression in the stroma was an independent negative predictive factor for response on chemotherapy, while CD4 and TIM-3 expression in lymphoid aggregates were independent prognostic factors for better outcome. Our data propose TIM-3 as a promising new target in mesothelioma. Chemotherapy influences the expression of immune checkpoints and therefore further research on the best combination treatment schedule is required.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

et al. 2016

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“…1) [85]. Oncogenic activation of PKB increases the expression PD-L1 in gliomas, lung cancers and colon cancers in an mTOR-dependent fashion [85][86][87]. Conversely, selective inhibition of PKB with small molecules downregulates PD-L1 expression [85].…”

Section: Role Of Tumor-derived Pkb Activity In Cancer Immune Surveillmentioning

confidence: 99%

PKB/Akt-dependent regulation of inflammation in cancer

Tang

Wang

Hemmings

et al. 2018

Seminars in Cancer Biology

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A B S T R A C TChronic inflammation is a major cause of human cancer. Clinical cancer therapies against inflammatory risk factors are strategically determined. To rationally guide a novel drug development, an improved mechanistic understanding on the pathological connection between inflammation and carcinogenesis is essential. PI3K-PKB signaling axis has been extensively studied and shown to be one of the key oncogenic drivers in most types of cancer. Pharmacological inhibition of the components along this signaling axis is of great interest for developing novel therapies. Interestingly, emerging studies have shown a close association between PKB activation and inflammatory activity in the vicinity of the tumor, and either blockade of PKB or attenuation of para-tumoral inflammation reveals a mutual-interactive pattern through pathway crosstalk. In this review, we intend to discuss recent advances of PKB-regulated chronic inflammation and its potential impacts on tumor development.

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“…This likely activates the STING pathway, which again is essential for PD-1/PD-L1 signaling. Another possible mechanism is as follows: the PI3K-Akt pathway is also reported to be important for PD-L1 activation (30)(31)(32), possibly through PTEN inactivation (33,34). It has recently been rediscovered that the PTEN-PI3K-Akt pathway is indispensable in DNA damage repair (35,36).…”

Section: Discussionmentioning

confidence: 99%

The Positive Relationship Between γH2AX and PD-L1 Expression in Lung Squamous Cell Carcinoma

Osoegawa

Hiraishi

Hashimoto

et al. 2018

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Abstract. Background Lung cancer, which is a leading cause of cancer death worldwide, is associated with a poor survival, even when the tumor is surgically removed. In terms of histology, lung squamous cell carcinoma, which accounts for 22% of the cases of resected lung cancer, is associated with poorer overall survival, with a five-year survival rate of approximately 60% in comparison to adenocarcinoma, which is the most common histological type (68%) and which has a five-year survival rate of approximately 75% (1). Molecular targeting therapies have recently been developed and have shown promising results against advanced lung cancer. Among the various types of lung cancer, lung squamous cell carcinoma has fewer treatment options because it is driven by alterations of tumor suppressor genes and subsequent chromosomal instability rather than oncogenic mutations (2). The chromosomal instability results in accumulation of somatic mutations and DNA damage response (3). This may explain why carcinogen-induced cancer, like lung squamous cell carcinoma and melanoma, is often accompanied by inflammation, as the DNA damage response is a major trigger activating the innate immune response. This consequence has been closely examined in the immune elimination process during viral infection and recently in the cancer immunity cycle (4).The activation of the innate immune response leads to activation of immune checkpoint molecules as a mechanism of immune escape. Programmed death-ligand 1 (PD-L1) is one of the immune checkpoint molecules that are expressed on the surface of tumor cells. Once it is expressed on the tumor cells, PD-L1 binds to its receptor, PD-1, on the membrane of the cytotoxic T cell and inhibits T cell activity, resulting in the escape of the tumor cell from the immune system (5). The recent development of therapies against immune checkpoint molecules, namely, CTLA-4, PD-1 and PD-L1 has shown that PD-1/PD-L1 blockade can improve overall survival in patients with cancer including malignant melanoma, lung squamous cell carcinoma, and lung adenocarcinoma (6-13).During the DNA damage response process, γH2AX, a unique histone subunit, serves as a sensor of double-stranded DNA damage, thereby gathering other proteins to form DNA damage repair complex foci (14). γH2AX foci are formed through irradiation, UV exposure, and cytotoxic chemotherapy, and the overexpression of γH2AX is common among various types of cancer. We hypothesized that the 171 This article is freely accessible online.Correspondence to: Ass. Prof.

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Control of PD-L1 Expression by Oncogenic Activation of the AKT–mTOR Pathway in Non–Small Cell Lung Cancer

Cited by 602 publications

References 53 publications

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

PKB/Akt-dependent regulation of inflammation in cancer

The Positive Relationship Between γH2AX and PD-L1 Expression in Lung Squamous Cell Carcinoma

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