Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: Significance in claudin-low breast cancer cells

Purpose: The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially affect clinical outcome in nonsmall cell lung cancer (NSCLC), an extended analysis of PD-L1 and tumor-infiltrating lymphocytes (TIL) was performed.Experimental Design: Samples from resected adenocarcinoma (ADC 42), squamous cell carcinoma (SCC 58), and 26 advanced diseases (13 ADC and 13 SCC) treated with nivolumab were analyzed. PD-L1 expression and the incidence of CD3, CD8, CD4, PD-1, CD57, FOXP3, CD25, and Granzyme B TILs were immunohistochemically assessed.Results: PD-L1 levels inversely correlated with N involvement, although they did not show a statistically significant prognostic value in resected patients. The incidence and phenotype of TILs differed in SCC versus ADC, in which EGFR and KRAS mutations conditioned a different frequency and tissue localization of lymphocytes. NSCLC resected patients with high CD8 pos lymphocytes lacking PD-1 inhibitory receptor had a longer overall survival (OS: HR ¼ 2.268; 95% CI, 1.056-4.871, P ¼ 0.03). PD-1-to-CD8 ratio resulted in a prognostic factor both on univariate (HR ¼ 1.952; 95% CI, 1.34-3.12, P ¼ 0.001) and multivariate (HR ¼ 1.943; 95% CI, 1.38-2.86, P ¼ 0.009) analysis. Moreover, low PD-1 incidence among CD8 pos cells was a distinctive feature of nivolumab-treated patients, showing clinical benefit with a prolonged progressionfree survival (PFS: HR ¼ 4.51; 95% CI, 1.45-13.94, P ¼ 0.004).Conclusions: In the presence of intrinsic variability in PD-L1 expression, the reservoir of PD-1-negative effector T lymphocytes provides an immune-privileged microenvironment with a positive impact on survival of patients with resected disease and response to immunotherapy in advanced NSCLC.

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“…These findings suggest additional roles of PD-L1 in tumor biology, including epithelial to mesenchymal transition (EMT; ref. 49). …”

Section: Discussionmentioning

confidence: 99%

Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

Mazzaschi

Madeddu

Falco

et al. 2018

Clinical Cancer Research

191

148

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“…Many recent studies have highlighted the critical role of PD-L1 in regulating the biological functions of cancer cells themselves, including cell proliferation, migration, metastasis, chemo/radio-resistance, and the promotion of epithelial to mesenchymal transition [9,10,18,21,23,[30][31][32]. It has been suggested that signal pathways such as JAK/ STAT1/IRF-1, MEK/ERK/STAT1 and PKD2 etc.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, a study carried out by Alsuliman et al indicated that induction of epithelial to mesenchymal transition in human mammary epithelial cells up-regulated PD-L1 expression mainly through activation of the PI3K/AKT pathway [10]. In another study, it was shown that PD-L1 expression could induce epithelial-to-mesenchymal transition in renal cell carcinoma by activating the transcription factor SREBP-1c [22].…”

Section: Introductionmentioning

confidence: 99%

“…Outside of the negative regulation associated with PD-L1 expression in the T cellmediated anti-tumor response, the contribution of PD-L1 expression in regulating the biological behaviors of the tumor cells themselves, such as proliferation, apoptosis, migration and resistance to chemo/radio-therapy, is still not clearly understood [8][9][10][11][12][13][14]. Our recent study has shown that knockdown of PD-L1 expression in the human gastric cancer cell line, SGC-7901, could significantly suppress cell proliferation, migration and tumor growth in the subcutaneous transplantation mouse model [15].…”

Section: Introductionmentioning

confidence: 99%

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PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

Chen

Xiong

et al. 2017

Cell Physiol Biochem

100

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Background/Aims: PD-L1 (Programmed cell death 1 ligand 1, PD-L1), an essential immune checkpoint molecule in the tumor microenvironment, is an important target for cancer immunotherapy. We have previously reported that its expression in human gastric and esophageal cancer tissues is significantly associated with cancer progression and patients' postoperative prognoses. Its expression in cancer cells is well known to inhibit the T cellmediated anti-tumor response, and this mechanism of action has been targeted for cancer immunotherapy. As of now, the autonomous effect of PD-L1 on cancer cells is not well understood, thus our present study aimed to examine the role of PD-L1 intervention in cellular biological functions, especially epithelial to mesenchymal transition (EMT), of the human esophageal cancer cell line, Eca-109 cells. Methods: Immunohistochemistry assay was used to investigate the correlation between expression of PD-L1 and EMT markers in human esophageal cancer tissues. Intervention of PD-L1 by using RNAi and over-expression methods were used to study the role of PD-L1 in regulation of biological behaviors and EMT in Eca-109 cells. Results: Our clinical and pathological data demonstrated that tumor samples in the EMT positive subgroup had higher PD-L1 expression than those in the EMT negative subgroup. By manipulating PD-L1 expression in Eca-109 cells either through ablation or overexpression of wild type and the cytoplasmic domain-truncated mutant, we demonstrated that PD-L1 expression significantly promoted the cell viability, migration and EMT phenotype. Furthermore, our study also indicated that PD-1 fusion protein mediated stimulation of PD-L1 and the cytoplasmic domain of PD-L1 played a critical role in promoting EMT phenotype of Eca-109 cells, thereby suggesting that PD-1 receptor usually by triggering the reverse signaling can effect PD-L1 mediated regulation of esophageal cancer cell response. Conclusion: Our present study reveals a tumor cell-autonomous role of PD-L1 signaling in promoting EMT in human esophageal cancer.L. Chen and Y. Xiong contributed equally to this work.

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“…74,75 PD-L1 is expressed in a significant number of TNBCs. [76][77][78][79][80] Early clinical trials are investigating the efficacy of anti-PD-1 pathway antibodies in TNBC. 20 Our unpublished data show that about 50% of TNBCs have positive PD-L1 staining in tumor or intratumoral stromal cells.…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

New Developments in Breast Cancer and Their Impact on Daily Practice in Pathology

Li¹,

Oprea‐Ilies²,

Krishnamurti

2017

Archives of Pathology &Amp; Laboratory Medicine

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Advances in research have transformed our understanding of breast cancers and have altered the daily practice of pathology. Theranostic evaluations performed by pathologists are now critical in triaging the patients into appropriate treatment groups, as are new guidelines that were recently established for the evaluation of HER2/neu gene amplification. Emerging molecular classifications of breast cancers bring novel perspectives to the assessment of individual cases, and opportunities for better treatments. Molecular studies have particularly shed light on distinct biological subsets of triple-negative breast cancers, for which new targeted therapies are being developed. The prognostic and therapeutic utility of new histopathologic parameters, such as tumor-infiltrating lymphocytes, are also being elucidated, and new protocols have been devised for the pathologic evaluation of breast specimens that have undergone neoadjuvant treatment. Novel clinical practices, such as radioactive seed localization, also affect the way breast specimens are processed and evaluated. In this brief review, we highlight the developments that are most relevant to pathology and are changing or could potentially impact our daily practice.

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Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: Significance in claudin-low breast cancer cells

Cited by 233 publications

References 38 publications

Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

New Developments in Breast Cancer and Their Impact on Daily Practice in Pathology

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