Prognostic and clinical impact of PD-L2 and PD-L1 expression in a cohort of 437 oesophageal cancers

Okadome, Kazuo; Baba, Yoshifumi; Nomoto, Daichi; Yagi, Taisuke; Kalikawe, Rebecca; Harada, Kazuto; Hiyoshi, Yukiharu; Nagai, Yoshinori; Ishimoto, Takatsugu; Iwatsuki, Masaaki; Iwagami, Shiro; Miyamoto, Yuji; Yoshida, Naoya; Watanabe, Masayuki; Komohara, Yoshihiro; Shono, Toshiyuki; Sasaki, Yutaka; Baba, Hideo

doi:10.1038/s41416-020-0811-0

Cited by 42 publications

(36 citation statements)

References 43 publications

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“…In head and neck squamous cell carcinoma, PD‐L2 status has been reported to be a significant predictor of progression‐free survival with pembrolizumab independently of PD‐L1 36 . We have recently reported that the expression of PD‐L2 as well as PD‐L1 is associated with unfavorable clinical outcomes in esophageal cancer 37 . We have also found that PD‐L2 and PD‐L1 exhibit distinct expression patterns during tumor development and variations in responses to chemotherapeutic agents.…”

Section: Programmed Death‐ligand 2 Expression On Cancer Cellsmentioning

confidence: 83%

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

et al. 2020

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Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD‐L1 expression on tumors, tumor‐infiltrating lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.

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Section: Programmed Death‐ligand 2 Expression On Cancer Cellsmentioning

confidence: 83%

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

et al. 2020

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“…Though this is was mainly in squamous cell carcinoma, the authors found no significant correlation between PD-L2 and PD-L1 expression. However, these data may indicate evaluation of both PD-L2 and PD-L1 expression may be clinically important [31].…”

Section: Discussionmentioning

confidence: 98%

The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation

et al. 2020

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Background: Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification. Methods: Three hundred twenty-nine EAC cases were available in Tissue Microarrays (TMA) format. A discovery cohort of 166 EAC cases were stained immunohistochemically for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS, IDO-1, PD-L1, PD-1). A validation cohort of 163 EAC cases was also accessed. A digital pathology analysis approach was used to quantify biomarker density. Results: CD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively). Correlation and multivariate analysis identified high CD45RO/ICOS patients with significantly improved OS which was independently prognostic (HR = 0.445, (0.223-0.886), p = 0.021). Assessment of CD45RO and ICOS high cases in the validation cohort revealed an associated with improved OS (HR = 0.601 (0.363-0.996), p = 0.048). Multiplex IHC identified cellular co-expression of high CD45RO/ICOS. High CD45RO/ICOS patients have significantly improved OS. Conclusions: Multiplexing identifies true cellular co-expression. These data demonstrate that co-expression of immune biomarkers are associated with better outcome in EAC and may provide evidence for immunotherapy treatment stratification.

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“…Due to low response rates among EC patients, however, further efforts are needed to elucidate the resistance mechanism of immunotherapy. Among all the patients with EC, less than 20% of them express PD-L1 ( Okadome et al, 2020 ), which means a certain number of patients with EC are hard to get any therapeutic benefit from immune checkpoint inhibitors. Moreover, the expression of PD-L1 on the cell surface was found to be highly heterogeneous in EC ( Yan et al, 2019 ).…”

Section: Cellular Componentsmentioning

confidence: 99%

“…Notably, the combination of PD-L1 expression and TILs status has the potential to serve as predictive biomarkers for patients with EC ( Yagi et al, 2019a ). PD-L2 has also been demonstrated to be associated with a worse prognosis in EC ( Ohigashi et al, 2005 ; Okadome et al, 2020 ). The identification of these biomarkers contributes not only to prognosis prediction but also to patient classification and selection ( Baba et al, 2020 ).…”

Section: Cellular Componentsmentioning

confidence: 99%

Advances in Drug Resistance of Esophageal Cancer: From the Perspective of Tumor Microenvironment

Luan

Zeng

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Drug resistance represents the major obstacle to get the maximum therapeutic benefit for patients with esophageal cancer since numerous patients are inherently or adaptively resistant to therapeutic agents. Notably, increasing evidence has demonstrated that drug resistance is closely related to the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic and ever-changing complex biological network whose diverse cellular and non-cellular components influence hallmarks and fates of tumor cells from the outside, and this is responsible for the development of resistance to conventional therapeutic agents to some extent. Indeed, the formation of drug resistance in esophageal cancer should be considered as a multifactorial process involving not only cancer cells themselves but cancer stem cells, tumor-associated stromal cells, hypoxia, soluble factors, extracellular vesicles, etc. Accordingly, combination therapy targeting tumor cells and tumor-favorable microenvironment represents a promising strategy to address drug resistance and get better therapeutic responses for patients with esophageal cancer. In this review, we mainly focus our discussion on molecular mechanisms that underlie the role of TME in drug resistance in esophageal cancer. We also discuss the opportunities and challenges for therapeutically targeting tumor-favorable microenvironment, such as membrane proteins, pivotal signaling pathways, and cytokines, to attenuate drug resistance in esophageal cancer.

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Prognostic and clinical impact of PD-L2 and PD-L1 expression in a cohort of 437 oesophageal cancers

Cited by 42 publications

References 43 publications

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation

Advances in Drug Resistance of Esophageal Cancer: From the Perspective of Tumor Microenvironment

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