Induction of PD-L1 Expression by the EML4–ALK Oncoprotein and Downstream Signaling Pathways in Non–Small Cell Lung Cancer

Ota, Keiichi; Azuma, Koichi; Kawahara, Akihiko; Hattori, Satoshi; Iwama, Eiji; Tanizaki, Junko; Harada, Taishi; Matsumoto, Koichiro; Takayama, K.; Takamori, Shinzo; Kage, Masayoshi; Hoshino, Tomoaki; Nakanishi, Yoichi; Okamoto, Isamu

doi:10.1158/1078-0432.ccr-15-0016

Cited by 398 publications

(340 citation statements)

References 37 publications

(45 reference statements)

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“…Various oncogenic pathways contribute to the intrinsic expression of PD-L1, such as the EML4-ALK oncoprotein in non-small cell lung cancer and loss of PTEN in glioma. 36,37 Extrinsic PD-L1 expression is thought to be induced by cytokines, especially IFNg, in the tumor environment via various downstream pathways. [17][18][19] Because PD-L1 expression in PeSCC cells can be either intrinsic or extrinsic, studies investigating the precise pathways involved are currently underway in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

Deng

Guo

et al. 2017

OncoImmunology

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Despite its rare incidence worldwide, penile squamous cell carcinoma (PeSCC) still presents with significant morbidity and mortality due to the limited treatment options for advanced patients, especially those in developing countries. The program death-1 (PD-1)/PD-1 ligand (PD-L1) axis has been demonstrated to play an important role in tumor immune escape, and immunotherapies targeting this pathway have shown great success in certain cancer types. Here, we analyzed the expression pattern of PD-L1 in tumor cells and tumorinfiltrating lymphocytes (TILs) in PeSCC with a multi-center cohort. We found that the majority of PeSCCs (53.4%) were PD-L1-positive and that high PD-L1 expression in tumor cells was associated with a poor prognosis. Notably, PD-L1 expression in tumor cells was significantly associated with the extent of TILs and CD8 C TILs. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) showed that PD-L1 was positively correlated with interferon-gamma (IFNg) and CD8 C gene expression. Moreover, we defined the constitutive and inducible surface expression of PD-L1 in newly established primary PeSCC cell lines. Interestingly, two PeSCC cell lines had high intrinsic PD-L1 expression. Another cell line showed low PD-L1 expression, but the PD-L1 expression could be induced by IFNg stimulation. Overall, our data showed that high PD-L1 expression in penile tumor cells indicated a poor prognosis. The upregulation of PD-L1 in PeSCC included both extrinsic and intrinsic mechanisms. These findings indicated that the PD-1/PD-L1 axis might be a potential therapeutic target for patients with penile squamous cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

Deng

Guo

et al. 2017

OncoImmunology

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“…1 The former refers to the upregulation of PD-L1 expression as a result of constitutive oncogenic signaling within tumor cells, as seen in ALKrearranged and EGFR-mutant lung cancer. 15,16 By contrast, adaptive immune resistance refers to the induction of PD-L1 expression on tumor cells in response to local inflammatory signals (eg, interferons) produced by active anti-tumor immune response (cytotoxic T cell and/or Th1 pathway activation). 13 This in turn induces PD-1 expression on T cells.…”

Section: Pd-l1 Expression In Colorectal Cancermentioning

confidence: 99%

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

et al. 2016

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Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape (adaptive immune resistance), and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression. We performed immunohistochemistry for PD-L1 on 181 cases of colorectal carcinoma with known microsatellite instability and mutational status, and correlated PD-L1 expression with clinicopathologic features including tumor-infiltrating lymphocyte burden/immunophenotype, tumor mutational profile, and disease-specific survival. PD-L1 was expressed in tumors from 16 patients (9%) who were more often older (P = 0.006) and female (P = 0.035), with tumors exhibiting a larger size (P = 0.013), but lower stage (Po0.001). PD-L1 expression was associated with increased CD8 and TBET-positive tumor-infiltrating lymphocytes, medullary phenotype, poor differentiation, microsatellite instability, BRAF mutation (Po 0.001 for each), and a lower frequency of KRAS mutation (P = 0.012). On multivariate analysis, PD-L1 expression was associated with medullary morphology and frequent CD8-positive tumor-infiltrating lymphocytes, suggesting adaptive immune resistance. PD-L1 positivity was not predictive of survival in the entire cohort, but it was associated with a lower disease-specific survival within the microsatellite-instability high cohort. PD-L1 expression in colorectal carcinoma is associated with clinicopathologic and molecular features of the serrated pathway of colorectal carcinogenesis, and is associated with a worse outcome within microsatellite-unstable tumors. These findings support the role of PD-L1 expression in providing normally immunogenic colorectal carcinoma a means of immune evasion and a more aggressive biology, provide a potential mechanistic explanation for the favorable response of microsatellite-unstable colorectal carcinoma to PD-1/PD-L1 pathway blockade, and suggest potential predictive and prognostic roles of PD-L1 immunohistochemistry in colorectal carcinoma.

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“…PD-L1 expression is significantly higher in ALK rearranged NSCLCs compared to NSCLCs with EGFR or KRAS mutation or to those with no genetic alteration of ALK, EGFR or KRAS (triple negative) (45,46). Interestingly, EGFR and ALK tyrosine kinase inhibitors (TKIs) directly inhibit tumor cell viability and indirectly enhance antitumor immunity through the PD-L1 downregulation (40,47,48). PD-L1 expression is related with better response to EGFR and ALK TKIs (45,49,50).…”

Section: Introductionmentioning

confidence: 99%

The combination of checkpoint immunotherapy and targeted therapy in cancer

Karachaliou¹,

Cao²,

Sosa³

et al. 2017

Ann. Transl. Med.

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Abstract:The therapeutic possibilities for patients with metastatic melanoma have changed due to the development of targeted therapies that inhibit oncogenic signaling pathways as well as immune modulating therapies that unleash the patient antitumor immunity. These therapeutic changes have impressively increased the median overall survival of the patients. Considering the dramatic but transient responses that occur with targeted therapies for a subgroup of patients and the durable responses that can be achieved with immunotherapy in a subset of patients, a lot of effort is ongoing for the clinical development of combinations of these two therapeutic approaches. Herein we discuss the existing preclinical and clinical data for the combination of targeted therapies and immunotherapy focusing mainly on melanoma and non-small cell lung cancer (NSCLC).

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Induction of PD-L1 Expression by the EML4–ALK Oncoprotein and Downstream Signaling Pathways in Non–Small Cell Lung Cancer

Cited by 398 publications

References 37 publications

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

The combination of checkpoint immunotherapy and targeted therapy in cancer

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