The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by α-PD-L1 or α-IL6 antibodies

Rolvering, Catherine; Zimmer, Andreas; Ginolhac, Aurélien; Margue, Christiane; Kirchmeyer, Mélanie; Servais, Florence; Hermanns, Heike M.; Hergovits, Sabine; Nazarov, Petr V.; Nicot, Nathalie; Kreis, Stephanie; Haan, Serge; Behrmann, Iris; Haan, Claude

doi:10.1002/jlb.ma1217-495r

Cited by 12 publications

(9 citation statements)

References 111 publications

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“…As deactivation of IFNGR1 did not lead to the downregulation of the PD-L1 and MHC-I molecules on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vivo compared to TC-1 and TC-1/A9 cells, respectively, we hypothesized that besides IFN-γ, other cytokines induced PD-L1 and MHC-I expression. Several studies have indicated the involvement of different factors (IFN-α, IFN-β, IL-27, EGF, TNF-α, IL-6, GM-CSF, IL-1α, and CCL2 combined with lipocalin 2) in PD-L1 and MHC-I stimulation or stabilization [27,[29][30][31][32][33][34][35][36][37][38][39]. In this study, type I IFNs (IFN-α and IFN-β) were the main inducers of PD-L1 and MHC-I expression.…”

Section: Discussionmentioning

confidence: 99%

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Vackova

Piatakova

Poláková

et al. 2020

IJMS

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Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of the interferon (IFN)-γ receptor 1 (IFNGR1) in tumor cells can interfere with anti-PD-L1 therapy. For this purpose, we used the mouse oncogenic TC-1 cell line expressing PD-L1 and major histocompatibility complex class I (MHC-I) molecules and its TC-1/A9 clone with reversibly downregulated PD-L1 and MHC-I expression. Using the CRISPR/Cas9 system, we generated cells with deactivated IFNGR1 (TC-1/dIfngr1 and TC-1/A9/dIfngr1). In tumors, IFNGR1 deactivation did not lead to PD-L1 or MHC-I reduction on tumor cells. From potential inducers, mainly IFN-α and IFN-β enhanced PD-L1 and MHC-I expression on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vitro. Neutralization of the IFN-α/IFN-β receptor confirmed the effect of these cytokines in vivo. Combined immunotherapy with PD-L1 blockade and DNA vaccination showed that IFNGR1 deactivation did not reduce tumor sensitivity to anti-PD-L1. Thus, the impairment of IFN-γ signaling may not be sufficient for PD-L1 and MHC-I reduction on tumor cells and resistance to PD-L1 blockade, and thus should not be used as a single predictive marker for anti-PD-1/PD-L1 cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Vackova

Piatakova

Poláková

et al. 2020

IJMS

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“…With regards to tackling the potential pro-tumor activity of IL-27, several studies have shown that IL-27 can regulate the immunosuppression and exhaustion of T cells. For example, IL-27 could also induce indoleamine 2,3-dioxygenase (IDO) and PD-L1 expression on monocytes and tumor-associated macrophages and on human prostate, breast and lung cancer cells [147][148][149][150]. Moreover, IL-27 signaling in human ovarian cancer cells activated STAT1/STAT3 and induced the constitutive expression of IDO [149].…”

Section: Il-27 In Cancer Immunotherapymentioning

confidence: 99%

IL-12 Family Cytokines in Cancer and Immunotherapy

Mirlekar

Pylayeva-Gupta

2021

Cancers

184

102

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The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.

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“…This concept is further supported by work in EBI3 and IL-27R KO mice demonstrating that IL-27 directly enhances Treg activity by inducing CD39 expression, resulting in tumor growth (116). Additionally, IL-27 stimulation induces PD-L1 expression on several types of cancer cells including: prostate, lung, and hepatocellular carcinoma (117, 118). PD-L1 expression is also induced by IL-27 in immune cell populations such as T cells and myeloid cells (119–121).…”

Section: Il-27 Il-30 and Il-35: Influencing Cancer Developmentmentioning

confidence: 99%

IL-27, IL-30, and IL-35: A Cytokine Triumvirate in Cancer

et al. 2019

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The role of the immune system in anti-tumor immunity cannot be overstated, as it holds the potential to promote tumor eradication or prevent tumor cell escape. Cytokines are critical to influencing the immune responses and interactions with non-immune cells. Recently, the IL-12 and IL-6 family of cytokines have accumulated newly defined members each with specific immune functions related to various cancers and tumorigenesis. There is a need to better understand how cytokines like IL-27, IL-30, and IL-35 interact with one another, and how a developing tumor can exploit these interactions to enhance immune suppression. Current cytokine-based immunotherapies are associated with cytotoxic side effects which limits the success of treatment. In addition to this toxicity, understanding the complex interactions between immune and cancer cells may be one of the greatest challenges to developing a successful immunotherapy. In this review, we bring forth IL-27, IL-30, and IL-35, “sister cytokines,” along with more recent additions to the IL-12 family, which serve distinct purposes despite sharing structural similarities. We highlight how these cytokines function in the tumor microenvironment by examining their direct effects on cancer cells as well their indirect actions via regulatory functions of immune cells that act to either instigate or inhibit tumor progression. Understanding the context dependent immunomodulatory outcomes of these sister cytokines, as well as their regulation within the tumor microenvironment, may shed light onto novel cancer therapeutic treatments or targets.

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The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by α-PD-L1 or α-IL6 antibodies

Cited by 12 publications

References 111 publications

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

IL-12 Family Cytokines in Cancer and Immunotherapy

IL-27, IL-30, and IL-35: A Cytokine Triumvirate in Cancer

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