Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

Marzec, Michał; Zhang, Qian; Goradia, Ami; Raghunath, Puthiyaveettil N.; Liu, Xiaobin; Paessler, Michele; Wang, Hong Yi; Wysocka, Maria; Cheng, Mangeng; Ruggeri, Bruce; Wasik, Mariusz A.

doi:10.1073/pnas.0810958105

Cited by 629 publications

(526 citation statements)

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“…Consistent with this, ALK activity by NPM-ALK translocation induced PD-L1 (CD274) expression in T-cell lymphoma. 34 Thus, these results imply that ALK translocation might contribute to the PD-L1 and PD-L2 expression in pulmonary adenocarcinomas, although the number of patients with ALK translocation included in this study was too small for this result to reach statistical significance. In this study, PD-L1 and PD-L2 expression were significantly and independently associated with MET expression.…”

Section: Discussionmentioning

confidence: 69%

“…6,34 During antitumor immune responses in vivo, various immune and tumor cells produce cytokines that upregulate PD-L1 (CD274) extrinsically in a paracrine and/or autocrine manner. 6,35 In contrast, an intrinsic mechanism refers to constitutive PD-L1 expression by oncogenic signaling, such as NPM-ALK translocation, PI3K/Akt activation, or chronic viral infection, 26,34,36 suggesting that intrinsic genetic alterations in tumor cells might account for regulation of the PD-1/PD-L pathway. Moreover, several driver mutations have emerged as therapeutic targets for patients with pulmonary adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

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Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

et al. 2015

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Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1 + and CD8 + tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (Po 0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P = 0.006), smokers (P = 0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (Po0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P = 0.054) and expression of EGFR and MET (Po 0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P = 0.052), and expression of MET (Po 0.001) and ERBB2 (P = 0.013). The numbers of CD8 + and programmed cell death-1 + lymphocytes were higher in smokers (P = 0.012 and 0.016) and MET-expressing adenocarcinomas (Po 0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1 + /CD8 + lymphocytes showed shorter disease-free survival (P = 0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

et al. 2015

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“…There is also evidence that PD-L1 expression can be driven by oncogenic signaling pathways as is the case with PTEN deletion in glioblastomas 44 and constitutive anaplastic lymphoma kinase signaling in lung cancers, which drive PD-L1 expression through signal transducer and activator 3 (STAT3) signaling. 45 PTEN deletions are often seen in microsatellite unstable colorectal carcinoma 46 and STAT3 overexpression was observed in our initial gene expression analysis (Supplementary data). Interestingly, in our immunohistochemical analysis, epithelial tumor cell expression of PD-L1 was similar across all categories with a slight statistically non-significant increase in epithelial staining of medullary carcinoma and microsatellite unstable tumors.…”

Section: Discussionmentioning

confidence: 88%

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Friedman

Brodsky

et al. 2016

Modern Pathology

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Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n = 105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (Po 0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (Po 0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups (P o0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.

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“…NPM/ALK executes its oncogenicity by activating a number of signal transduction proteins, including signal transducer and activator of transcription 3 (STAT3) (Zhang et al, 2002;Chiarle et al, 2008;Li and Morris, 2008). The continuous activation of these signal transmitters leads to the persistent modulation of target genes, the protein products of which govern key cell functions, such as proliferation, apoptosis and, as we have recently shown, evasion of the anti-tumor immune response (Kasprzycka et al, 2006;Marzec et al, 2008), as well as the expression of NPM/ALK itself (Zhang et al, 2007;Wasik et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

et al. 2010

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Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

Cited by 629 publications

References 36 publications

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

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