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Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T-cell leukemia/lymphoma.

ABSTRACT: Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK-STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression-free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.

SUBMITTER: Morichika K

PROVIDER: S-EPMC6726676 | biostudies-other | 2019 Sep

REPOSITORIES: biostudies-other

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Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T-cell leukemia/lymphoma.

Morichika Kazuho K Karube Kennosuke K Kayo Hirona H Uchino Shuta S Nishi Yukiko Y Nakachi Sawako S Okamoto Shiki S Morishima Satoko S Ohshiro Kazuiku K Nakazato Iwao I Fukushima Takuya T Masuzaki Hiroaki H

Cancer science 20190723 9

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK-STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), p ...[more]

PMID: 31237072

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Project description:BACKGROUND:Antitumor immune response of programmed cell death ligand (PD-L1) has shown clinical value not only in Hodgkin lymphoma and EBV-associated lymphomas but also in EBV-negative diffuse large B cell lymphoma (DLBCL) of non-germinal center B cell-like (non-GCB) subtype. Signal transducer and activator of transcription 3 (STAT3) is known to induce PD-L1 in immune cells and its activated form, phosphorylated STAT3 (pSTAT3), is also frequently expressed in non-GCB DLBCL. Herein, we investigated associations between PD-L1 expression/gene alteration, pSTAT3 expression and clinicopathologic variables in EBV-negative DLBCL. METHODS:In 107 cases of DLBCLs with non-GCB subtype (67%; 72/107), GCB subtype (25%; 27/107) and unclassifiable cases (8%; 8/107), we performed PD-L1 and pSTAT3 immunohistochemistry and fluorescence in situ hybridization for PD-L1 gene translocation and copy number gain/amplification. RESULTS:PD-L1 was expressed in tumor cells (PD-L1t) in 21% (23/107; 30% cutoff), immune cells (PD-L1i) in 36% (38/107; 20% cutoff), and pSTAT3 in tumor nuclei in 41% (44/107; 40% cutoff). PD-L1 gene alteration was observed in 10% (10/102) including translocation in 6% (6/102) and copy number gain/amplification in 4% (4/102). Non-GCB subtype was associated with PD-L1t and pSTAT3 (p?=?0.006 and p?=?0.042), and tended to have PD-L1 gene alteration (p?=?0.058). Tumoral PD-L1 expression without gene alteration (PD-L1t+ GA-) correlated with pSTAT3-positive tumor cell proportions (%) (p?=?0.033). In survival analysis, pSTAT3 expression independently predicted shorter PFS in total cohort (p?=?0.017) and R-CHOP-treated group (p?=?0.007), and in pSTAT3-negative R-CHOP-treated subset, PD-L1 expression in immune cells (PD-L1i) correlated with shorter PFS (p?=?0.042). CONCLUSIONS:Gene alteration and protein expression of PD-L1 and pSTAT3 expression were closely related in DLBCL and constituted features of non-GCB subtype. In addition to known clinical significance of pSTAT3, immune cell expression of PD-L1 (PD-L1i) had also clinical value in pSTAT3-dependent manner. These findings may provide an insight into immunotherapeutic strategy and risk stratification in DLBCL patients.

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Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T-cell leukemia/lymphoma.

Publications

Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T-cell leukemia/lymphoma.

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