Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma

Högner, Anica; Thuss‐Patience, Peter

doi:10.3390/ph14020151

Cited by 20 publications

(21 citation statements)

References 47 publications

(63 reference statements)

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“…The disruption of the PD-1/PD-L1 interaction by immune checkpoint therapeutic antibodies (Abs) against PD-1 and PD-L1 reactivates antitumor T-cells, resulting in an antitumor effect [ 12 ]. Despite the great success of immune checkpoint therapies blocking the PD-1/PD-L1 interaction in a small subset of various cancer patients [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], the treatment failed in most cases, including in CRC patients, due to intrinsic unresponsiveness and/or acquired resistance [ 21 , 22 , 23 , 24 , 25 , 26 ]. Specifically, the early clinical trials demonstrated that patients with CRC appeared to be poor responders to immune checkpoint therapies [ 27 , 28 , 29 ], indicating an urgent need for novel immunotherapeutic strategies against CRC.…”

Section: Introductionmentioning

confidence: 99%

Role of Ezrin/Radixin/Moesin in the Surface Localization of Programmed Cell Death Ligand-1 in Human Colon Adenocarcinoma LS180 Cells

et al. 2021

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Programmed cell death ligand-1 (PD-L1), an immune checkpoint protein highly expressed on the cell surface in various cancer cell types, binds to programmed cell death-1 (PD-1), leading to T-cell dysfunction and tumor survival. Despite clinical successes of PD-1/PD-L1 blockade therapies, patients with colorectal cancer (CRC) receive little benefit because most cases respond poorly. Because high PD-L1 expression is associated with immune evasion and poor prognosis in CRC patients, identifying potential modulators for the plasma membrane localization of PD-L1 may represent a novel therapeutic strategy for enhancing the efficacy of PD-1/PD-L1 blockade therapies. Here, we investigated whether PD-L1 expression in human colorectal adenocarcinoma cells (LS180) is affected by ezrin/radixin/moesin (ERM), functioning as scaffold proteins that crosslink plasma membrane proteins with the actin cytoskeleton. We observed colocalization of PD-L1 with all three ERM proteins in the plasma membrane and detected interactions involving PD-L1, the three ERM proteins, and the actin cytoskeleton. Furthermore, gene silencing of ezrin and radixin, but not of moesin, substantially decreased the expression of PD-L1 on the cell surface without affecting its mRNA level. Thus, in LS180 cells, ezrin and radixin may function as scaffold proteins mediating the plasma membrane localization of PD-L1, possibly by post-translational modification.

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Section: Introductionmentioning

confidence: 99%

Role of Ezrin/Radixin/Moesin in the Surface Localization of Programmed Cell Death Ligand-1 in Human Colon Adenocarcinoma LS180 Cells

et al. 2021

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“…During the last few years, cancer immunotherapy has demonstrated promising results with different types of tumors [9][10][11][12]. In particular, with the introduction of immune checkpoint inhibitor (ICI)-targeted immunotherapy, the immunotolerant tumor microenvironment can be overcome by reactivating T cells, enhancing anti-tumor immunity, and eliminating tumor cells more effectively [13].…”

Section: Introductionmentioning

confidence: 99%

PD-L1/PD-1 and CTLA-4 Expression in Equine Penile Squamous Cell Carcinomas

Porcellato

Mecocci

Brachelente

et al. 2021

Animals

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In horses, penile squamous cell carcinomas (epSCCs) are among the most common cutaneous neoplastic lesions. These tumors usually arise in benign lesions such as viral plaques and papillomas frequently induced by Equus caballus papillomavirus type 2 (EcPV2) infection. In the last decade, the introduction of immune checkpoint inhibitors (ICI) for the treatment of human cancers has demonstrated promising results. Among the most commonly targeted pathways, there is PD-1/PD-L1 and CTLA-4. The aim of this study is to investigate the expression of the PD-1/PD-L1 pathway and CTLA-4 in the tumor microenvironment of epSCCs to assess the feasibility of an immunotherapeutic approach. Twenty equine epithelial tumors were retrospectively selected and submitted to RT-qPCR for PD-1 and PD-L1 genes. After testing antibodies cross-reactivity by western blotting, immunohistochemistry for PD-L1 and CTLA-4 was performed. Results from RT-qPCR demonstrated that 3/20 cases expressed the PD-L1 gene, whereas the PD-1 gene was not detected. Immunohistochemical positivity for PD-L1 was found only in one case. CTLA-4-positive cells were observe in all cases but were few (Mdn = 4.8; IQR = 2.3–7.1 cells/HPF). In this study group, PD-1/PD-L1 and CTLA-4 do not appear to be highly expressed and therefore the use of ICI in epSCCs may not have promising rates of response.

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“…Differential immune cell infiltration patterns in the 2 EC types may help explain their different response to ICIs. ESCC patients receiving a selective PD-1 inhibitor (i.e., nivolumab) showed improved disease-free survival in the adjuvant therapy setting (CHECKMATE-557) (45). In first-line treatment, PD-1-inhibitor (pembrolizumab) combined with chemotherapy significantly prolonged OS time for ESCC patients (KEYNOTE-590) (45).…”

Section: Discussionmentioning

confidence: 99%