Tumor inherent interferons: Impact on immune reactivity and immunotherapy

Brockwell, Natasha K.; Parker, Belinda S.

doi:10.1016/j.cyto.2018.04.006

Cited by 20 publications

(13 citation statements)

References 114 publications

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“…The increased response to IFNs found in the microarrays in T3-treated MCF7-TRb cells is particularly interesting, as these molecules are implicated in tumor immune surveillance and induce the expression of immune checkpoint proteins (41). Thus, through modulating the response to IFN, TRb could potentially regulate immunotherapeutic responses.…”

Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Receptor β Inhibits Self-Renewal Capacity of Breast Cancer Stem Cells

López-Mateo

Alonso-Merino

Suárez-Cabrera³

et al. 2020

Thyroid

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Background: A subpopulation of cancer stem cells (CSCs) with capacity for self-renewal is believed to drive initiation, progression, and relapse of breast tumors. Methods: Since the thyroid hormone receptor b (TRb) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that TRb could affect the CSC population using MCF-7 cells grown under adherent conditions or as mammospheres, as well as inoculation into immunodeficient mice. Results: Treatment of TRb-expressing MCF-7 cells (MCF7-TRb cells) with the thyroid hormone triiodothyronine (T3) decreased significantly CD44 + /CD24and ALDH + cell subpopulations, the efficiency of mammosphere formation, the self-renewal capacity of CSCs in limiting dilution assays, the expression of the pluripotency factors in the mammospheres, and tumor initiating capacity in immunodeficient mice, indicating that the hormone reduces the CSC population present within the bulk MCF7-TRb cultures. T3 also decreased migration and invasion, a hallmark of CSCs. Transcriptome analysis showed downregulation of the estrogen receptor alpha (ERa) and ER-responsive genes by T3. Furthermore, among the T3-repressed genes, there was an enrichment in genes containing binding sites for transcription factors that are key determinants of luminaltype breast cancers and are required for ER binding to chromatin. Conclusion: We demonstrate a novel role of TRb in the biology of CSCs that may be related to its action as a tumor suppressor in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Receptor β Inhibits Self-Renewal Capacity of Breast Cancer Stem Cells

López-Mateo

Alonso-Merino

Suárez-Cabrera³

et al. 2020

Thyroid

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“…20–22 Type I IFNs induce a multitude of interferon regulated genes (IRGs) that can impact accumulation, activation, and function of immune cells, and also directly act on tumor cells via anti-proliferative and pro-apoptotic functions. 21,23–25 Loss of host IFN signaling, global or cell specific, has been linked to cancer initiation, progression, and metastasis in a number of solid malignancies. 26–29 Our previous studies in breast cancer discovered tumor cell intrinsic interferon signaling as a critical mediator of the anti-tumor immune response, 29 the loss of which promotes immune escape and bone metastasis.…”

Section: Introductionmentioning

confidence: 99%

Tumor inherent interferon regulators as biomarkers of long-term chemotherapeutic response in TNBC

et al. 2019

Self Cite

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Patients diagnosed with triple negative breast cancer (TNBC) have an increased risk of rapid metastasis compared to other subtypes. Predicting long-term survival post-chemotherapy in patients with TNBC is difficult, yet enhanced infiltration of tumor infiltrating lymphocytes (TILs) has been associated with therapeutic response and reduced risk of metastatic relapse. Immune biomarkers that predict the immune state of a tumor and risk of metastatic relapse pre- or mid-neoadjuvant chemotherapy are urgently needed to allow earlier implementation of alternate therapies that may reduce TNBC patient mortality. Utilizing a neoadjuvant chemotherapy trial where TNBC patients had sequential biopsies taken, we demonstrate that measurement of T-cell subsets and effector function, specifically CD45RO expression, throughout chemotherapy predicts risk of metastatic relapse. Furthermore, we identified the tumor inherent interferon regulatory factor IRF9 as a marker of active intratumoral type I and II interferon (IFN) signaling and reduced risk of distant relapse. Functional implications of tumor intrinsic IFN signaling were demonstrated using an immunocompetent mouse model of TNBC, where enhanced type I IFN signaling increased anti-tumor immunity and metastasis-free survival post-chemotherapy. Using two independent adjuvant cohorts we were able to validate loss of IRF9 as a poor prognostic biomarker pre-chemotherapy. Thus, IRF9 expression may offer early insight into TNBC patient prognosis and tumor heat, allowing for identification of patients that are unlikely to respond to chemotherapy alone and could benefit from further immune-based therapeutic intervention.

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“…Type I IFNs have emerged as central coordinators of tumor–immune-system interactions, including stimulation of anti-tumor effector cells (T cells, NK cells, dendritic cells), and negative regulation of suppressive cells (MDSCs and Treg cells) [56]. Recent studies have shown that the expression and secretion of tumor-inherent IFNs is a key player in the anti-tumor immune cascade, influencing the immunogenicity, progression and therapeutic response of tumors [57]. Unfortunately, impaired interferon signaling has been reported to be a common defect in human cancer [3], but the mechanisms underlying tumor-inherent IFN dysfunction have not been determined.…”

Section: Discussionmentioning

confidence: 99%

NOS1 inhibits the interferon response of cancer cells by S-nitrosylation of HDAC2

et al. 2019

J Exp Clin Cancer Res

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BackgroundThe dysfunction of type I interferon (IFN) signaling is an important mechanism of immune escape and metastasis in tumors. Increased NOS1 expression has been detected in melanoma, which correlated with dysfunctional IFN signaling and poor response to immunotherapy, but the specific mechanism has not been determined. In this study, we investigated the regulation of NOS1 on the interferon response and clarified the relevant molecular mechanisms.MethodsAfter stable transfection of A375 cells with NOS1 expression plasmids, the transcription and expression of IFNα-stimulated genes (ISGs) were assessed using pISRE luciferase reporter gene analysis, RT-PCR, and western blotting, respectively. The effect of NOS1 on lung metastasis was assessed in melanoma mouse models. A biotin-switch assay was performed to detect the S-nitrosylation of HDAC2 by NOS1. ChIP-qPCR was conducted to measure the binding of HDAC2, H4K16ac, H4K5ac, H3ac, and RNA polymerase II in the promoters of ISGs after IFNα stimulation. This effect was further evaluated by altering the expression level of HDAC2 or by transfecting the HDAC2-C262A/C274A site mutant plasmids into cells. The coimmunoprecipitation assay was performed to detect the interaction of HDAC2 with STAT1 and STAT2. Loss-of-function and gain-of-function approaches were used to examine the effect of HDAC2-C262A/C274A on lung metastasis. Tumor infiltrating lymphocytes were analyzed by flow cytometry.ResultsHDAC2 is recruited to the promoter of ISGs and deacetylates H4K16 for the optimal expression of ISGs in response to IFNα treatment. Overexpression of NOS1 in melanoma cells decreases IFNα-responsiveness and induces the S-nitrosylation of HDAC2-C262/C274. This modification decreases the binding of HDAC2 with STAT1, thereby reducing the recruitment of HDAC2 to the ISG promoter and the deacetylation of H4K16. Moreover, expression of a mutant form of HDAC2, which cannot be nitrosylated, reverses the inhibition of ISG expression by NOS1 in vitro and decreases NOS1-induced lung metastasis and inhibition of tumor infiltrating lymphocytes in a melanoma mouse model.ConclusionsThis study provides evidence that NOS1 induces dysfunctional IFN signaling to promote lung metastasis in melanoma, highlighting NOS1-induced S-nitrosylation of HDAC2 in the regulation of IFN signaling via histone modification.

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Tumor inherent interferons: Impact on immune reactivity and immunotherapy

Cited by 20 publications

References 114 publications

Thyroid Hormone Receptor β Inhibits Self-Renewal Capacity of Breast Cancer Stem Cells

Thyroid Hormone Receptor β Inhibits Self-Renewal Capacity of Breast Cancer Stem Cells

Tumor inherent interferon regulators as biomarkers of long-term chemotherapeutic response in TNBC

NOS1 inhibits the interferon response of cancer cells by S-nitrosylation of HDAC2

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