PD-1 and PD-L1 Expression in NSCLC Indicate a Favorable Prognosis in Defined Subgroups

Schmidt, L. H.; Kümmel, Andreas; Görlich, Dennis; Möhr, Michael; Bröckling, Sebastian; Mikesch, Jan Henrik; Grünewald, Inga; Marra, Alessandro; Schultheis, Anne M.; Wardelmann, Eva; Müller‐Tidow, Carsten; Spieker, Tilmann; Schliemann, Christoph; Berdel, Wolfgang E.; Wiewrodt, Rainer; Hartmann, Wolfgang

doi:10.1371/journal.pone.0136023

Cited by 218 publications

(184 citation statements)

References 33 publications

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“…It is in line with a recent report, showing that PD-1 þ T infiltrating lymphocytes and PD-L1 þ tumor cells were both favorable prognostic factors in ovarian cancer (41). The inverse function of the immune checkpoint molecules in controlling the T-cell activation in other types of cancers was also suggested by several other independent studies (42)(43)(44). As a matter of fact, some of the B7-CD28 members, such as CTLA-4, have been reported to brake T regulatory cell proliferation driven by CD28 (45) or to inhibit CD28 costimulation by depleting the ligands (46).…”

Section: Discussionsupporting

confidence: 90%

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer

Kreuzinger

Geroldinger

Smeets

et al. 2017

Clinical Cancer Research

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Purpose: Most high-grade serous ovarian cancer (HGSOC) patients develop recurrent disease after first-line treatment, frequently with fatal outcome. This work aims at studying the molecular biology of both primary and recurrent HGSOC. Experimental Design: Gene expression profiles of matched primary and recurrent fresh-frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. Clustering analyses and pairwise comparison of the profiles between matched samples and subsequent functional alignment were used for the identification of molecular characteristics of HGSOC. Results: Both primary and recurrent HGSOC samples presented predominant gene expression differences in their microenvironment, determined by a panel of genes covering all major pathways of immune activation together with a number of genes involved in the remodeling of extracellular matrix and adipose tissues. Stratifying tumor tissues into immune active and silent groups, we further discovered that although some recurrent tumors shared the same immune status as their primary counterparts, others switched the immune status, either from silent to active or active to silent. Interestingly, genes belonging to the B7-CD28 immune checkpoint family, known for their major role as negative regulators of the immune response, were overexpressed in the immune active tumors. Searching for potential tumor antigens, CEACAM21, a member of the carcinoembryonic antigen family, was found to be significantly overexpressed in immune active tissues in comparison with the silent ones. Conclusions: The results illustrate the complexity of the tumor microenvironment in HGSOC and reveal the molecular relationship between primary and recurrent tumors, which have multiple therapeutic implications. Clin Cancer Res; 23(24); 7621–32. ©2017 AACR.

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Section: Discussionsupporting

confidence: 90%

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer

Kreuzinger

Geroldinger

Smeets

et al. 2017

Clinical Cancer Research

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“…Most studies have emphasized an association between high PD-L1 expression and poor survival based on the ability of PD-L1 to negatively regulate antitumor T-cell responses. In contrast, high PD-L1 expression has been linked to better prognosis in some malignancies (17,35,37). In these reports, a significant association between high PD-L1 expression and increased TILs was identified (17,34,35,37).…”

Section: Discussionmentioning

confidence: 93%

“…The prognostic value of PD-L1 expression has been investigated for various malignancies, including malignant melanoma, nonsmall cell lung cancer, and renal cell carcinoma (34)(35)(36). Most studies have emphasized an association between high PD-L1 expression and poor survival based on the ability of PD-L1 to negatively regulate antitumor T-cell responses.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma

Yokoyama

Miyoshi

Nakashima

et al. 2016

Clinical Cancer Research

115

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Purpose: The immune checkpoint of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is believed to play an important role in evasion of host antitumor immune surveillance in various malignancies; however, little is known about its role in thymic carcinoma. This study investigated PD-1/PD-L1 expression and its association with clinicopathologic features, the expression of immune-related proteins in tumor-infiltrating lymphocytes (TIL), and patient prognosis. Experimental Design: PD-L1 and PD-1 expression was evaluated by IHC in 25 thymic carcinoma tissue specimens. Copy number alterations of the PD-L1 gene in 11 cases were assessed in formalin-fixed, paraffin-embedded material using qRT-PCR. Results: Compared with normal subjects, 3 thymic carcinoma patients showed an increase in PD-L1 copy number, whereas 8 did not. PD-L1 was significantly overexpressed in cases with copy number gain as compared with normal cases. High PD-L1 expression was associated with higher disease-free and overall survival rates as compared to cases with low expression. Prognostic analysis revealed low PD-L1 expression and high number of PD-1+ TILs as significant predictors of poor survival, together with Masaoka–Koga stage IVa/IVb disease and incomplete resection. In the quantitative analysis of TILs, PD-L1 expression correlated proportionally with the number of infiltrating CTLs. Conclusions: Here, for the first time, we report that PD-L1 and PD-1 expression might be useful prognostic predictors in thymic carcinoma. Further studies are expected to substantiate the prognostic value of PD-L1 and PD-1 expression, and the potential efficacy of targeting the PD-1/PD-L1 pathway in thymic carcinoma via immunotherapy. Clin Cancer Res; 22(18); 4727–34. ©2016 AACR.

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“…There are some studies suggesting a negative prognostic role (17,(21)(22)(23), while others did not find any prognostic value (24,25). However, other studies reported improved patient outcomes (20,26). This discrepancy may be due to different PD-L1 immunohistochemistry assays, using variable detection antibodies and different cutoff.…”

Section: Resultsmentioning

confidence: 99%

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

Rashed

Abdelrahman²,

Abdelgawad³

et al. 2017

TJPATH

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IntRoduCtIonLung cancer ranks the first in the incidence and mortality rates amongst all malignancies worldwide. Non-small cell lung cancer (NSCLC) constitutes 80% -85% of all diagnosed cases and more than 70% of NSCLC are diagnosed as an advanced or late disease (1).Recognition of tumor antigens by t cells leads to activation of anti-tumor immune reaction mainly by cytotoxic CD+8 tumor infiltrating lymphocytes (tiLs), but malignant cells may have many pathways to evade the immunological destruction. PD-1 is a co-stimulatory molecule on t-cells that inhibits t cell activation. PD-1, which is a 288-amino acid cell-surface protein, can bind two ligands, PD-L1 and PD-L2, which negatively control the immune response. tumor cells express PD-L1 can inhibit t cell-mediated immune response and can progress to distant metastasis (2,3). CD8 marker is expressed on cytotoxic t cells, natural killer, and dendritic cells. CD8+ t cells are a major component of the cell-mediated immune system against malignant cells. CD8+ t cells undergo differentiation to effector cytotoxic t cells. Then the effector CD8+ cells undergo apoptosis leaving memory cells when a pathogenic response is resolved. Memory t cells and cytotoxic t cells are associated with a more favorable prognosis in NSCLC (4).PD-L1 over-expression has been proved to be a poor prognostic marker in many human cancers (5). PD-1/ PD-L1 interaction suppresses CD8+ tiLs survival and proliferation and leads to apoptosis of tumor-infiltrating lymphocytes. PD-L1 over-expression in tumor cells in a syngeneic transplant model of tumor cells makes them evade from cytotoxic tiLs (6). AbStRACtObjective: Programmed cell death ligand-1 interacts with the immune receptors on the surface of CD8+ tumor infiltrating lymphocytes and PD-1, thereby blocking its anti-tumor activity. therapeutics suppression of this interaction will show a promise in the treatment of non-small cell lung cancer by restoring the functional anti-tumor t-cell activity. We aimed to evaluate the association between the immunohistochemical expression of PD-L1, stromal CD8+ tumor infiltrating lymphocytes and p53 with the clinicopathological characteristics, response to chemotherapy, progression-free-survival, and overall survival. Material and Method:We examined the immunohistochemical expression of PD-L1, stromal CD8+ tiLs, and p53 expression in 50 patients with advanced stage (iii&iV) non-small cell lung cancer.Results: PD-L1 was expressed in 56% of the studied cases. PD-L1 expression was related to unfavorable response to the therapy without significant difference. PD-L1 expression was significantly associated with disease progression, poor progression-free-survival & overall survival. CD8+ tiLs were high in 32% of the cases. tumors with high CD8+ tiLs showed a partial response to therapy and had a better progression-free-survival and overall survival. p53 expressed in 82% of the studied cases. there was a significant negative association between PD-L1 and CD8+ tiLs (p=0.009), while a non-significant association wa...

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PD-1 and PD-L1 Expression in NSCLC Indicate a Favorable Prognosis in Defined Subgroups

Cited by 218 publications

References 33 publications

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

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