Interferon-γ-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression

Bellucci, Roberto; Martin, Allison; Bommarito, Davide; Wang, Kathy; Hansen, Steen Ingemann; Freeman, Gordon J.; Ritz, Jérôme

doi:10.1080/2162402x.2015.1008824

Cited by 260 publications

(226 citation statements)

References 50 publications

(55 reference statements)

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“…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%

“…16 Cytokines, especially interferon-gamma (IFNg), that are expressed by activated T cells can induce PD-L1 expression in the surrounding tumor cells via specific signaling pathways. [17][18][19] To better elucidate the correlation between PD-L1 expression and TILs in PeSCC, the mRNA expression levels of PD-L1, IFNg, and CD8 C were evaluated in 24 primary penile cancer specimens. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed a significant positive correlation between PD-L1 and IFNg or CD8 C ( Fig.…”

Section: Correlation Between Pd-l1 Expression and Ifng In Pesccmentioning

confidence: 99%

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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%

Section: Correlation Between Pd-l1 Expression and Ifng In Pesccmentioning

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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“…However, the same IFN-γ signaling processes can ultimately induce feedback inhibition that compromises antitumor immunity (11). As part of this feedback loop, IFN-γ signaling enables the PD-1 signaling axis to become activated through direct upregulation of the ligands PD-L1 and PD-L2 in tumor, immune infiltrate, and stromal cells, which interact with PD-1 on tumor-infiltrating T cells to downregulate the cytotoxic response (12)(13)(14). In addition, IFN-γ can upregulate expression of other key immune suppressive molecules such as IDO1 within the tumor microenvironment (15).…”

Section: Introductionmentioning

confidence: 99%

IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade

Ayers¹,

Lunceford²,

Nebozhyn³

et al. 2017

Journal of Clinical Investigation

2,744

104

2,669

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“…113 PD-1 blockade may thus promote anti-tumor immunity by facilitating NK cell recognition of MHC-I deficient RS cells, and this effect has been seen in primary hematopoietic cancer cells 114 ( Figure 2A). Meanwhile, Tregs are actually activated by PD-1 ligand binding, 115,116 suggesting that the suppression of Treg function may be another potential immunomodulatory effect of anti-PD-1 therapy ( Figure 2B).…”

mentioning

confidence: 99%

The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

Vardhana

Younes

2016

Haematologica

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Interferon-γ-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression

Cited by 260 publications

References 50 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

IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade

The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

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