Nuclear Receptors in Cancer Inflammation and Immunity

TREIMM 1644 No. of Pages 14

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Review

Nuclear Receptors in Cancer Inflammation and Immunity Linjie Zhao,1 Hongbo Hu,2 Jan-Åke Gustafsson,3,4,* and Shengtao Zhou1,* Members of the nuclear receptor (NR) superfamily orchestrate cellular processes that can impact on numerous cancer hallmarks. NR activity plays important roles in the tumor microenvironment by controlling inflammation and immune responses. We summarize recent insights into the diverse mechanisms by which NR activity can control tumor inflammation, the roles of different NRs in modulating tumor immunity, and the biological features of immune cells that express specific NRs in the context of cancer. NR-dependent alterations in tumor inflammation and immunity may be amenable to pharmacological manipulation and offer new clues regarding the development of novel cancer therapeutic regimens.

Highlights NR fine-tune physiological and pathological processes by acting as sensors of stimuli and orchestrating downstream molecular events that govern complex gene regulatory networks. The roles of dysregulated NR-mediated signaling pathways in tumorigenesis have been well documented in a variety of cancer types. Inflammatory responses in tumor microenvironments induced by oncogenic viruses or bacterial infections, autoimmune reactions, or altered gut microbiota homeostasis can be controlled by NRs.

NRs in the Modulation of Cancer Inflammation and Immunity NRs are transcription factors that control a wide array of essential biological functions such as cell growth and death, embryonic development, cellular metabolism, immune reactions, and inflammatory processes [1]. A total of 48 members of this superfamily have been identified in Homo sapiens so far [2] (Table 1); they sense environmental stimuli rapidly and coordinate a variety of responses in both physiological and diseased states. Pioneering work initially linked steroid hormones to prostate cancer and subsequently to breast cancer [3], prompting further investigations into the roles of the NR superfamily in various cancers. Tumorigenesis and cancer progression have been linked in some instances to inflammatory processes caused by pathogen infection [4]. For instance, chronic inflammation induced by persistent oncogenic pathogen infections – such as human papillomavirus (HPV), Epstein–Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Helicobacter pylori – can dramatically elevate the risk for developing cancer in humans [4–7]. With our evolving understanding of inflammation-induced carcinogenesis, the role of NRs in the modulation of pathogen infection (e.g., HPV) and related cancer inflammation has been increasingly appreciated (Figure 1 and Table 2). Apart from the active involvement of NRs in cancer inflammation, the roles of these receptors in cancer immunity are less well understood. On the one hand, some immune cells express NRs [e.g., NR subfamily 4 group A member 1 (NR4A1+) monocytes and ROR-γt+ T helper type 17 (Th17) cells; see Glossary], and thus might respond to NR modulation in the form of either activation or repression [8,9]. On the other hand, the ligand-binding activity for NRs in cancer cells can lead to transactivation or transrepression of a set of target genes, resulting in the release of secreted proteins or metabolites from cancer cells into the extracellular niche [10] (Figure 2, Key Figure). Indeed, it is well known that the NR superfamily is actively involved in cancer development and progression because oncogenic signaling depends on NR-mediated transcriptional regulation. Recently, accumulating evidence has highlighted a crucial role of NRs in immunity and inflammation, particularly in the context of cancer. Therefore, the processes of NR modulation of immune cells together with the activation of NR-mediated signaling in cancer cells can shape the Trends in Immunology, Month 2019, Vol. xx, No. xx

NRs can control immune reactions or influence specific immune cell subsets to regulate different cancer-related features. NR superfamily factors constitute promising therapeutic targets for cancer treatments by modulating inflammation or immunity, either locally or systematically.

1

Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education (MOE), and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, and Collaborative Innovation Center, Chengdu, PR China 2 Department of Rheumatology and Immunology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, PR China 3 Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA

https://doi.org/10.1016/j.it.2019.12.006 © 2019 Elsevier Ltd. All rights reserved.

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Table 1. Human NR Superfamily Members and Their Natural Ligands Name

Nomenclature

Symbol

Ligands

Steroid hormone receptors Estrogen receptor

3-Ketosteroid receptor

NR3A1

ESR1

Estradiols

NR3A2

ESR2

Estradiols, 5α-androstane-3β,17β-diol

NR3C1

GR

Cortisols (hydrocortisone)

NR3C2

MR

Aldosterone

NR3C3

PGR

Progesterone

NR3C4

AR

Testosterone, dihydrotestosterone

NR1A1

THRA

Thyroxine (T4), triiodothyronine (T3)

NR1A2

THRB

Thyroxine (T4), triiodothyronine (T3)

Nonsteroid hormone receptors Thyroid hormone receptor

Retinoic acid receptor

RAR-related orphan receptor

Vitamin D receptor

NR1B1

RARA

All-trans and 9-cis retinoic acid

NR1B2

RARB

All-trans and 9-cis retinoic acid

NR1B3

RARC

All-trans and 9-cis retinoic acid

NR1F1

RORA

Oxysterols

NR1F2

RORB

Cholesterol, cholesterol sulfate

NR1F3

RORC

Retinoic acid

NR1I1

VDR

Calcitriol (1',25'-dihydroxy vitamin D3)

Adopted orphans Peroxisome proliferator-activated receptor

Reverse ErbA

Liver X receptor-like

Vitamin D receptor-like

Retinoid X receptor

Steroidogenic factor-like

NR1C1

PPARA

Fatty acids

NR1C2

PPARD

Fatty acids

NR1C3

PPARG

Fatty acids

NR1D1

REV-ERBa

Heme

NR1D2

REV-ERBb

Heme

NR1H2

LXRB

Oxysterols

NR1H3

LXRA

Oxysterols

NR1H4

FXR

Bile acids

NR1I2

PXR

Bile acids

NR1I3

CAR

Androstanol, androstenol

NR2B1

RXRA

9-Cis-retinoic acid

NR2B2

RXRB

9-Cis-retinoic acid

NR2B3

RXRG

9-Cis-retinoic acid

NR5A1

SF-1

Phospholipids

NR5A2

LRH-1

Phospholipids

DSS-AHC critical region on the X chromosome, gene 1

NR0B1

DAX-1

Unknown

Short heterodimeric partner

NR0B2

SHP

CD437 retinoids

Orphan NRs

Hepatocyte nuclear factor 4

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NR2A1

HNF4A

Fatty acids

NR2A2

HNF4G

Fatty acids

4 Center for Medical Innovation, Department of Biosciences and Nutrition at Novum, Karolinska Institute, Stockholm, Sweden

*Correspondence: [email protected] (J.-Å. Gustafsson) and [email protected] (S. Zhou).

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Table 1. (continued)

Glossary

Name

Nomenclature

Symbol

Ligands

Testicular orphan receptors

NR2C1

TR2

All-trans retinoic acid

NR2C2

TR4

All-trans retinoic acid

NR2E1

TLX

Not known

Tailless-related receptor Photoreceptor cell-specific receptor

NR2E3

PNR

Benzimidazoles

Chicken ovalbumin upstream promoter transcription factor

NR2F1

COUP-TF1

Not known

NR2F2

COUP-TF2

Retinol/ATRA

diversified tumor immune microenvironment niche. In this review, we revisit the functions of NRs in the control of tumor inflammation and immunity. We focus on estrogen receptors (ERs), androgen receptors (ARs), liver X receptors (LXRs), RAR-related orphan receptors (RORs), and NR4A1. The molecular features and role of immune cells that express specific NRs in cancer are also discussed. Owing to space constraints, and although no less important, we do not focus on farnesoid X receptors (FXRs), retinoid X receptors (RXRs), nuclear receptor subfamily 2 group F member 6 (NR2F6), or other family receptors.

Estrogen Receptors ERs, comprising ERα and ERβ, are actively involved in regulating the proliferation, survival, and migration of cancer cells (e.g., breast cancer) through multiple mechanisms [11–13]. However, ERα and ERβ demonstrate divergent biological effects. Whereas ERα primarily engages in a promalignant program in hormone-sensitive cancers, ERβ usually mediates proliferation arrest and growth inhibition in Homo sapiens [14]. ERs have been implicated in oncogenic virus-induced local or systemic inflammation. For instance, steroid hormone contraceptive use [15] and HPV infection [16] have been associated with increased cervical cancer risk in humans. In the process of HPV-induced progression from normalcy to cervical intraepithelial neoplasia (CIN) and cervical cancer, ERα expression in epithelial cells is decreased whereas ERα is continuously expressed in FSP1−CD34−SMA+ activated fibroblasts [17]. These fibroblasts can secrete CXCL1 and CXCL5 to activate CXCR2 expressed on cervical cancer cells to further promote cancer progression [17]. However, the mechanisms by which ERs directly modulate immune cells in the context of oncogenic virus infection remain unknown, warranting further investigation. ER Control of Tumor Immunity Using murine breast cancers in immunocompetent mice, and human breast cancers in immunodeficient mouse models, one study showed that estrogen increased the recruitment of lymphocyte function-associated antigen 1 (LFA-1)+ neutrophils to the invasive front of mouse mammary tumors, promoted transforming growth factor (TGF)-β1 production, and enhanced neutrophil infiltration in mammospheres, inducing LFA-1 overexpression in neutrophils relative to the control group [18]. In a zebrafish model, in the presence of estrogen, neutrophils facilitated the dissemination of ER+ breast cancer cells via LFA-1 and TGF-β1, given that anti-human TGF-β1 and anti-human LFA-1 antibodies significantly reduced the dissemination of MCF-7 cells even in the presence of estrogen and neutrophils, relative to controls [18]. This phenomenon indicated that this process transformed noninvasive breast cancer cells into highly metastatic cells; close interactions of neutrophils with cancer cells that drive breast cancer metastasis in this model

Androgen deprivation therapy (ADT): antihormone therapy used for the management of prostate cancer. Cervical intraepithelial neoplasia (CIN): cervical dysplasia; denotes the abnormal growth of cells on the surface of the cervix that could potentially progress towards cervical cancer. Chimeric antigen receptors (CARs): receptor proteins engineered to endow T cells the ability to target a specific protein of interest. The receptors are chimeric because they combine both antigen-binding and T cell-activating functions into a single receptor. Foam cells: a type of myeloid cells that contain cholesterol. They can form a plaque that results in atherosclerosis. Group 3 ILC3 cells: a subset of innate lymphoid cells defined by expression of the transcription factor ROR-γt. They are important for regulating inflammation, immunity, and immune cell development. Immune checkpoint blockade: immune checkpoints, such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), are regulators of the immune system that are crucial for selftolerance, which prevents the immune system from attacking cells indiscriminately. Immune checkpoint blockade therapy has been approved by the FDA for the treatment of a variety of tumor types. Inducible T cell co-stimulator (ICOS): a CD28 superfamily inducible co-stimulatory molecule that is expressed on activated T cells. Innate lymphoid cells (ILCs): a subset of recently discovered innate immune cells derived from common lymphoid progenitor (CLP) cells belonging to the lymphoid lineage. M1 macrophages: a subset of macrophages arbitrarily categorized as 'classically activated', typically by IFN-γ or lipopolysaccharide (LPS); they produce proinflammatory cytokines, phagocytose microbes, and initiate immune responses. M2 macrophages: a subset of macrophages that are arbitrarily categorized as 'alternatively activated' and named according to the previously discovered Th2 cell-mediated antiinflammatory response. They are activated via IL-4 and IL-13, and lead to inhibition of proinflammatory signals.

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were observed using time-lapse imaging [18]. Thus, estrogen can contribute to shaping the breast cancer tumor immune microenvironment. By contrast to ERα, our research group demonstrated that ERβ can hijack gene expression programs that favor an antitumor immune response. We found that selective activation of ERβ with a specific agonist, LY500307, could potently suppress lung metastatic colonization of triplenegative breast cancer (TNBC) and melanoma in mouse models [19]. LY500307 induced cell death in metastatic foci by recruiting and activating antitumor neutrophils in these foci. Depletion of neutrophils by anti-Ly6G antibody treatment in vivo abolished LY500307-mediated metastasis suppression in mice. Interleukin (IL)-1β released by LY500307-treated TNBC cells and melanoma cells was responsible for neutrophil chemotaxis in vitro. Collectively, these studies support the role of ERs as key regulators of neutrophil immune responses in the cancer microenvironment, suggesting that they might represent potential therapeutic targets in the clinical setting.

Androgen Receptor AR Control of HBV Infection and Hepatocellular Carcinoma Responses HBV is a sex hormone-responsive virus [20] because of its remarkable sex bias in HBV-related hepatocellular carcinoma (HCC) incidence – which is five- to sevenfold higher in male HBV human carriers than in female carriers [21]. This suggests that male gender constitutes a risk factor for HBV-associated hepatocarcinogenesis. Accordingly, hepatic AR accelerates HBVinduced hepatocarcinogenesis in HBV transgenic mice that lack AR in liver hepatocytes (HBVL-AR−/y) [22]. The reported mechanism of action is that hepatic AR increases the HBV viral titer by promoting HBV RNA transcription via direct binding to the androgen response element (ARE) near the viral core promoter [22]. This activity, together with its downstream target gene HBx, synergistically forms a feedback loop in promoting hepatocarcinogenesis [22]. Although the impact of AR on HBV or HCV infection has been studied, the impact of androgen and AR on immune cells and HBV infection remains largely unknown, partly because of the lack of adequate models [23]. AR in Prostate Cancer and Immunity Preclinical studies have implicated sustained AR signaling as a major driving force in the development of castration-resistant prostate cancer (CRPC), which led to the discovery of novel agents targeting the AR pathway that are now in widespread clinical use [24]. This androgen therapy resistance is reported to have intersections with potential immune effects which might pose therapeutic possibilities. Orchiectomy was found to synergize with CpG treatment, a Toll-like receptor (TLR)9 agonist reported to activate dendritic cells (DCs) for cross-priming in the B16OVA mouse tumor model [25]. By contrast, the more widely applied treatment of medical androgen deprivation therapy (ADT) involving AR antagonists impaired the therapeutic effects of immunotherapy in patients with prostate cancer [26]. In a prostate cancer mouse tumor model, the use of medical ADT unexpectedly dampened adaptive immunity by interfering with initial T cell priming rather than during the T cell reactivation or expansion phases [26]. This was evidenced using the OTI transgenic mouse tumor model: ex vivo splenocytes were stimulated with OTI peptide 6 h before flutamide (ADT) treatment, whereas in another group splenocytes were stimulated with OTI peptide 24 h before flutamide administration. Using a cytometric bead array (CBA) after 48 h, it was found that flutamide no longer inhibited cytokine production in splenocytes [IL-2 and interferon (IFN)] when drug addition was delayed by 24 h in vitro [26]. Thus, optimization of antiandrogen timing and dosing could be crucial for maximizing the antitumor effects of combined therapies. Recently, IL-23 produced by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was held to be a major cause of CRPC in both mice and human [27]. Mechanistically, MDSC-secreted IL-23 was reported to activate AR signaling in prostate tumor cells in a 4

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Mammospheres: clusters of mammary gland cells which form under specific conditions. Orchiectomy: surgery to remove one or both male testicles, commonly performed to treat or prevent prostate cancer from spreading. Patrolling monocytes (PMos): subsets include CX3CR1highLy6C− cells in mouse, and CX3CR1highCD14dimCD16+ cells in humans; they function in different disease states to scavenge damaged cells and debris from the vasculature and have been associated with wound healing, resolution of inflammation in damaged tissues, and suppression of cancer metastasis. Regulatory T cells (Tregs): a subgroup of immunosuppressive CD4+ T cells that modulate the immune system, maintain tolerance to selfantigens, and prevent autoimmune diseases. They generally suppress or downregulate the function and proliferation of effector T cells. Tc17 cells: a subset of interleukin 17secreting CD8+ T cells. T helper type 1 (Th1) cells: a lineage of CD4+ effector T cell defined by the production of IFN-γ; they promote cellmediated immune responses and are required for host defense against pathogens and tumors. T helper type 17 (Th17) cells: interleukin 17-secreting proinflammatory CD4+ T helper cells. Tolerant T cells: a subset of T cells in a state of unresponsiveness to substances or tissues; they have the capacity to elicit an immune response in a given organism.

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mouse model, thus favoring cell survival and proliferation in androgen-deprived conditions. Specifically, in prostate cancer cells kept in full androgen-deprivation medium, the addition of bone marrow (BM) MDSC conditioned medium from Il23a wild-type (WT) mice (IL23 WT BM-MDSCs) enhanced the proliferation and survival of prostate cancer cells, as well as the transcription of AR target genes, relative to medium from Il23a knockout mice (IL23 KO BM-MDSCs) [27]. Intratumor MDSC infiltration and IL-23 concentrations were elevated in blood and tumor samples from patients with CRPC [27]. Moreover, antibody-mediated IL-23 inactivation restored cancer cell sensitivity to ADT in PtenPC−/− tumor-bearing mice [27]. Collectively, MDSCs might induce CRPC development by acting in a non-cell-autonomous manner [27]. These findings are relevant because IL-23-based treatment might potentially oppose MDSC-mediated resistance to castration in prostate cancer – a common treatment in human prostate cancer patients – and ideally synergize with standard therapies.

Liver X Receptors LXRα and LXRβ are actively involved in the transcriptional control of mammalian lipid metabolism. LXR Influence on Antitumor Immunity The LXR-dependent effects of oxysterols on both inflammation and immunity in cancer have been explored. LXR activation triggers a variety of immune responses, implying that an oxysterol–LXR axis might be cell-, tissue-, and context-dependent [28]. This further complicates the network linking LXR-dependent oxysterol signaling, immune cells, and cancer hallmarks. The most intensively investigated immune cells influenced by LXRs in cancer are myeloid cells. 27Hydroxycholesterol (27HC), a primary metabolite deriving from cholesterol and also an ER and LXR ligand, promoted ER-dependent tumor growth and LXR-dependent metastatic behavior in both human MCF7 cell xenografts as well as in MMTV–PyMT mouse spontaneous breast cancer models [29]. The effects of cholesterol relied on the conversion to 27HC by the cytochrome P450 oxidase CYP27A1, which was reversed by CYP27A1 inhibitor administration [29]. Both tumor cells and tumor-associated macrophages showed high CYP27A1 expression in high-grade tumors. Thus, reducing blood cholesterol or blocking its conversion to 27HC might represent a strategy to prevent and treat breast cancer, although rigorous investigations are warranted in this front [29]. LXR might also be considered as a putative therapeutic target in melanoma [30]. Oral administration of multiple LXR agonists suppressed a number of malignant processes in human melanoma models [30,31]. LXRβ induction suppressed key melanoma phenotypes via extracellular apolipoprotein E (ApoE). Moreover, stromal ApoE was found to be necessary for LXRβ agonist GW3965-induced tumor growth suppression because melanoma tumors implanted into Apoe−/− mice demonstrated no growth reduction in response to GW3965 treatment. This suggested that the suppressive effects of LXR agonists in vivo might be further augmented by the activation of LXRs in stromal cells. Stromal cells might provide additional sources of extracellular ApoE to potentiate the antitumor properties of LXRβ agonists [30]. Moreover, using genetic and pharmacological strategies in multiple human and mouse cancer models, a pathway involving LXR control of PMN-MDSC infiltration was reported [32]. Therapeutic activation of LXR by RGX-104 significantly lowered PMN-MDSC abundance in murine B16F10 melanoma models and in advanced solid cancer patients (the first six evaluable patients enrolled in the trial included melanoma, sarcoma, and renal, uterine, and colorectal cancers) treated in a first-in-human, dose-escalation, multicenter Phase I triali [32]. Depletion of PMN-MDSCs further activated CD8+ cytotoxic T cell responses in mice and in these cancer patients relative to controls [32]. ApoE served as an LXR transcriptional target to mediate these effects in

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Figure 1. The Role of Nuclear Receptors in Oncogenic Virus Infection: The Human Papillomavirus (HPV) Example. In the process of HPV-induced transition from normalcy to cervical intraepithelial neoplasia (CIN) and cervical cancer, estrogen receptor α (ERα) expression in epithelial cells is decreased whereas ERα is continuously expressed in FSP1−CD34−SMA+ activated fibroblasts in cervical cancer. These fibroblasts can secrete CXCL1 and CXCL5 to activate CXCR2 expressed on cervical cancer cells to further promote cervical cancer progression. A straight arrow indicates activation of downstream targets. A blocking sign indicates inhibition of downstream targets.

mice, where LXR/ApoE activation therapy elicited potent antitumor responses and also enhanced CD8 + T cell activation under multiple immunotherapeutic regimens [32]. Although RGX-104 was well tolerated in these six patients with no dose-limiting toxicities, a clinical outcome of treated cancer patients was not reported. Nevertheless, these findings suggest that the LXR/ApoE axis may be important in the regulation of select innate immune responses, and might represent a candidate target for enhancing the efficacy of some cancer immunotherapies. Our research group has also provided evidence for the role of LXRs in cancer-associated immunity and inflammation. In a mouse model of peripheral squamous cell lung cancer (PSCCa), these tumors spontaneously developed in the absence of LXRα and LXRβ (Nr1h2−/−Nr1h3−/− mice) [33]. Foam cells progressively accumulated in the lungs of 3 month old LXRα/β double-knockout (DKO) mice, but no accumulation was noted in LXRα or LXRβ single-knockout (KO) mice [33]. Moreover, relative to WT mice, inflammatory cell enrichment and lipid deposition in the alveolar wall, as well as infiltration of type 2 pneumocytes and macrophages, were also noted in DKO mice [33]. Transcriptional analysis at the 12th month showed a remarkable increase in the expression of markers for M1 macrophages and lymphocytes (such as IL-6, CXCL10, CXCL16, etc.) relative to controls [33]. Aside from the impact of LXRs on macrophages in cancer, the functions of DCs were also reported to be fine-tuned by LXRs. Specifically, LXR ligands were secreted by human melanoma, colon, lung, and kidney tumor cell lines, as well as by mouse RMA tumor cells. These ligands further inhibited chemokine receptor CCR7 expression on maturing DCs and their subsequent chemotaxis to lymphoid organs in mice injected with DCs activated with lipopolysaccharide (LPS) in the presence of 22R-HC-, MR255-, LOVO-, or RMA-conditioned medium [34]. In addition, mice inoculated with MRS3, LOVO, and RMA tumors that expressed the LXR ligand-inactivating enzyme gene Sult2b1 significantly controlled tumor growth by reattracting DC migration to tumor-draining lymph nodes [34]. Tumor growth was also attenuated in chimeric mice transplanted with BM from LXRα KO (Nr1h3−/−) mice, which further implicated LXR ligand/ LXR interactions in tumor growth [34]. Collectively, the further mechanistic insight provided by these studies has drawn a promising blueprint for the future of LXR modulation in select immune-oncology therapies. 6

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Table 2. Human NRs Involved in Oncogenic Virus Infections Oncogenic virus

NR

Functions

Refs

Human papillomavirus

ER

Estrogen-treated HPV-infected cervical tissue is characterized by an inflammatory microenvironment; stromal ERs are crucial for HPV infection whereas epithelial ERs are dispensable

[60,61]

RAR

RARβ regulates HPV-induced chronic inflammation and decreases apoptosis in cervical cancer

[62]

AR

AR increases the HBV viral titer by enhancing HBV RNA transcription; cooperates with HBx protein; enhances hepatic telomerase reverse transcriptase gene transcription

[22,63]

Hepatitis B virus

Hepatitis C virus

Kaposi sarcoma-associated herpesvirus (KSHV)

Gammaherpesvirus

ER

ER protectively reduces HBV infection in cooperation with HNF4α

[64]

FXR

FXR reduces covalently closed circular DNA pool size; alters bile salt metabolism homeostasis to facilitate chronic HBV infection

[65]

RXR

RXR inhibits HBV infection at an early stage

[66]

HNF4α

HNF4α controls HCV-induced upregulation of glycolysis

[67]

PPARα

HNF4α controls HCV-induced upregulation of ketogenesis

[67]

FXR

HNF4α controls HCV-induced upregulation of ketogenesis

[67]

LXR

LXRs control low-density lipoprotein receptor (LDLR) expression through regulation of Idol expression

[68,69]

AR

Membrane-localized AR promotes the endocytosis and nuclear trafficking of KSHV; cooperatively activates Src/RSK1/EphA2 signaling to promote KSHV infection

[70]

GR

KSHV-derived LANA acts as a transcriptional coactivator of GR

[71]

LXR

LXRs suppress the expression of genes that are involved in fatty acid and cholesterol synthesis, two metabolic pathways that support gammaherpesvirus replication

[72]

RAR-Related Orphan receptors The ROR family comprises three members: ROR-α, ROR-β, and ROR-γ, encoded by Rora, Rorb, and Rorc, respectively. In particular, the RORC gene generates two different transcript variants in Homo sapiens [35]. RORC transcript variant 2 encodes one isoform, ROR-γt, that is primarily expressed in T cells and is a vital factor in the differentiation of naïve CD4+ T cells into Th17 cells [9]. The Jekyll and Hyde of ROR-γt+ Immune Cells in Cancer In addition to playing a role in inflammatory diseases, ROR-γt+ immune cells seem to play a dual role in carcinogenesis and tumor progression. On the one hand, ROR-γt+ T cells have been shown to mediate potent and durable tumor growth suppression when transferred into EG7 tumor-bearing animals [36]. Human Th17 cells stimulated with inducible T cell co-stimulator (ICOS) and redirected with a chimeric antigen receptor (CAR) construct showed prolonged tumor-killing activity in mice implanted with human mesothelioma. Activation of ROR-γt with small-molecule synthetic agonists was also reported to enhance the effector functions of Th17 cells and decrease immune-suppressive mechanisms, leading to improved antitumor efficacy in adoptive cell therapy (ACT) models and in syngeneic murine tumor models [36]. Recently, administration of a synthetic, small-molecule ROR-γt agonist, LYC-54143, during ex vivo expansion was found to promote the antitumor activity of human Th17 and Tc17 cells redirected with a CAR [37]. Similarly, ex vivo administration of this agonist enhanced the antitumor properties of murine tumor-specific CD4+ and CD8+ T cells relative to controls [37]. Other indirect evidence also indicates that some ROR-γt immune cells are tumor-suppressive: ubiquitin ligase Itch deficiency could result in the spontaneous development of colitis and increased susceptibility to colon cancer in mice [38]. Th17 cells, innate lymphoid cells (ILCs), and γδ T cells in Itch−/− mice expressed elevated amounts of IL-17 in the colonic mucosa relative to WT mice [38]. The suggested mechanism was that Itch can bind to ROR-γt and target ROR-γt for ubiquitination and degradation. Inhibition or genetic inactivation of ROR-γt reduced IL-17 expression and alleviated spontaneous colonic inflammation in Itch−/− mice relative to WT mice [38].

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Key Figure

A Holistic View of Nuclear Receptor (NR)–Ligand-Mediated Crosstalk between Immune and Nonimmune cells in the Tumor Microenvironment

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Figure 2. In cancer cells, NRs such as the estrogen receptor (ER)β, liver X receptor (LXR), and androgen receptor (AR) can control specific gene expression programs to modulate the secretion of factors that could educate immune cells in the tumor microenvironment. Meanwhile, these immune cells also express specific NRs [e.g., NR subfamily 4 group A member 1 (NR4A)1+ T cells, NR4A1+ patrolling monocytes, ROR-γt+ T cells, and ROR-γt+ group 3 innate lymphoid cells (ILC3) cells] and play either a tumor-promoting or a tumor-suppressing role in distinct contexts. A straight arrow indicates activation of downstream targets. A blocking sign indicates inhibition of downstream targets. A broken blocking sign refers to either suppression or activation of the targets. Abbreviations: G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; H3K27ac, histone H3 lysine 27 acetylation; LFA-1, lymphocyte function-associated antigen 1; MDSCs, myeloid-derived suppressor cells; mTOR, mammalian target of rapamycin; TGF, transforming growth factor; TNF, tumor necrosis factor.

Furthermore, a tumor-promoting role of ROR-γt+ immune cell has also been documented. Enhanced type 17 immune responses were observed in distal bile duct cancer (DBDC) patients, as evidenced by both the elevated concentrations of type 17 effector cytokines IL-17A and tumor necrosis factor (TNF)-α, and the proportion of CD8+ROR-γt+ T cells (Tc17 cells), in peripheral blood of DBDC patients relative to healthy controls [39]. CD8+ROR-γt+ T cells represent a highly activated subset that secreted IL-17A, as did CD4+ROR-γt+ T cells (Th17 cells). The majority of CD8+ROR-γt+ T cells coexpressed T-bet, a lineage transcription factor for T helper type 1 (Th1) and Tc1 development, suggesting that CD8+ROR-γt+ T cells might undergo a 8

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phenotypic switch toward a Tc17/1-like state with coproduction of IL-17A and IFN-γ [39]. CD8+ROR-γt+ T cells showed activated T cell receptor (TCR) signaling and were terminally differentiated and exhausted relative to CD8+ROR-γt− T cells. These cells also failed to regain perforin expression after degranulation, and demonstrated reduced cytotoxicity relative to CD8+ROR-γt− T cells ex vivo. Thus, blood CD8+ROR-γt+ T cells from these patients were deemed to be proinflammatory and functionally dysregulated relative to healthy individuals, thus potentially contributing to DBDC development [39]. In the human breast tumor microenvironment, infiltration of ROR-γt+ group 3 ILC3s was associated with an increased risk of lymph node metastasis [40]. CCL21-mediated chemotaxis of ILC3s to tumors triggered CXCL13 production by stromal cells in a preclinical mouse breast cancer model, and this reciprocally enhanced ILC3–stromal interactions and production of the cancer cell motile factor RANKL (receptor activator of nuclear factor κB ligand). ILC3 depletion or CCL21, CXCL13, or RANKL neutralization were sufficient to reduce lymph node metastasis relative to WT mice. Thus, this study established a role for ROR-γt+ ILC3s in facilitating cancer metastasis [40]. RORC1/ROR-γ has also been found to regulate tumor-promoting 'emergency' granulomonocytopoiesis. Cancer-driven granulomonocytopoiesis triggered the expansion of tumor-promoting myeloid subsets, primarily PMN-MDSCs and tumor-associated macrophages (TAMs) [41]. A specific subset of PMN-MDSCs and TAMs based on RORC1/ROR-γ expression patterns was also reported in human colorectal cancer and mouse murine fibrosarcoma carriers [41]. RORC1 regulates myelopoiesis by inhibiting negative (Socs3 and Bcl3) and bolstering positive (C/EBPβ) regulators of granulopoiesis, as well as modulating the major transcriptional mediators of myeloid progenitor commitment and differentiation to the monocyte/macrophage lineage (IRF8 and PU.1) [41]. In this study, RORC1 maintained tumor-promoting innate immunity by protecting PMN-MDSCs from apoptosis, triggering TAM differentiation and M2 macrophage polarization, and restraining tumor infiltration by mature neutrophils relative to RORC1-absent counterparts. Moreover, RORC1 depletion in the hematopoietic compartment suppressed cancer-driven myelopoiesis, leading to suppression of tumor growth and metastasis, given that tumor growth and metastasis were significantly reduced in Rorc1−/− versus WT chimeric mice (donor RORC1-deficient BM cells transplanted into lethally irradiated C57BL/6 WT recipient mice) [41]. These observations place a spotlight on ROR-γt+ immune cells as constituting a double-edged sword in cancer biology. Although we are currently nowhere near achieving a complete understanding of these mechanisms in cancer, we should be cautious about their contextspecific functions when we plan to move forward with ROR-γt-based therapeutic regimens into putative clinical trials.

NR Subfamily 4 Group A member 1 Another receptor of interest is the NR4A1, also termed Nur77/TR3/NGFIB. This is an orphan NR that controls cell proliferation and apoptosis [42]. Its involvement in cancer biology seems paradoxical because it has usually been considered to be tumor-suppressive [43,44], but in specific contexts, such as under metabolic stress, NR4A1 may contribute to tumor cell survival [45]. Similarly to its function in cancer cells, NR4A1 has seemingly contradictory roles in cancer immunity. NR4A1+ Monocytes in Cancer Immunity NR4A1 has been demonstrated to be indispensable for the survival of patrolling monocytes (PMos) in mouse models [46,47]. Recently, NR4A1+ PMos have been implicated in scavenging tumor cells, and consequently in controlling lung metastasis (Figure 3 and Table 3) [48]. The microvasculature of the lung is infiltrated with PMos, and these were shown to suppress tumor metastasis to the lung in preclinical mouse metastatic tumor models [48]. Specifically, NR4A1deficient mice lacking PMos suffered from increased lung metastasis relative to WT mice, as

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Figure 3. NR Subfamily 4 Group A Member 1 (NR4A1+) Patrolling Monocytes in Cancer Surveillance. NR4A1+ patrolling monocytes are recruited by endothelial cells expressing CX3CL1 in response to tumor cell accumulation. Nonmetastatic cells secrete exosomes that express high amounts of pigment epithelium-derived factor (PEDF) on the exosomal surface to induce NR4A1 expression in bone marrow monocytes precursors, and promote patrolling monocyte (PMo) expansion, to kill tumor cells. Interferon (IFN)-γ triggers an increase in chemokine CX3CL1 in the vessel lumen, promoting continuous crawling by human patrolling and proangiogenic monocytes, and making these monocytes insensitive to chemokines required for their extravasation. Expression of the angiogenic factor vascular endothelial growth factor (VEGF) and the inflammatory cytokine tumor necrosis factor (TNF) by tumor cells facilitates human patrolling and proangiogenic monocyte extravasation by inducing GATA3-mediated repression of CX3CL1 expression. After PMos extravasate into lung tissue, they express CCL3/4/5 and potentially recruit cytotoxic natural killer (NK) cells to kill the metastatic cancer cells. A straight arrow indicates activation of downstream targets. A blocking sign indicates inhibition of downstream targets.

evidenced in both melanoma and breast cancer mouse models [48]. Transfer of NR4A1proficient PMos into Nr4a1 KO mice abolished tumor invasion in the lung. Furthermore, exosomes shed from non-metastatic melanoma cells (ExoNM) were incorporated into the BM Table 3. NR-Positive Immune Cells in Cancer Biology NR-positive cells

Functions in cancer

Species

Refs

NR4A1+ monocytes cells

Also termed patrolling monocytes, they scavenge tumor cells and control metastasis in the lung

Homo sapiens and Mus musculus

[48,49]

NR4A1+ T cells

NR4A maintains the identity of Treg cells that suppress antitumor immunity

Homo sapiens and Mus musculus

[51–54]

ROR-γt+ T cells

The functions of ROR-γt+ T cells are controversial: they can mediate potent and durable tumor growth suppression; they may also be proinflammatory and functionally impaired, contributing to tumorigenesis

Homo sapiens and Mus musculus

[36,37,39]

ROR-γt+ ILC3

ROR-γt+ ILC3 cells stimulate the production of CXCL13 by stromal cells, which in turn promotes ILC3–stromal interactions and production of the cancer cell motile factor RANKL

Homo sapiens and Mus musculus

[40]

RXR+ myeloid cells

RXR+ myeloid cells can control lung metastasis formation while not affecting primary tumor growth

Mus musculus

[73]

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via CD11b+ myeloid cells, inducing PMo expansion [49]. This was demonstrated when exosome treatment led to a remarkable shift in the total myeloid population: ExoNM caused a significant increase in the Ly6Clow subpopulation, and a coordinate decrease in Ly6Chigh cells, relative to exosomes shed from metastatic melanoma cells (ExoM) [49]. High pigment epithelium-derived factor (PEDF) expression on the surface of ExoNM induced NR4A1 expression in BM monocyte precursors, promoted PMo expansion, recruitment, and the differentiation of TRAIL+ tumorreactive macrophages, which subsequently killed and phagocytized melanoma cells [49]. Indeed, exposure of macrophages exposed to ExoNM versus ExoM caused a significant increase in TRAIL mRNA relative to controls [49]. Recently, the mechanisms of extravasation of human patrolling and proangiogenic monocytes into tumors were reported [50]. Using human colorectal and breast tumor xenograft models and live imaging of transmigration, this study demonstrated that IFN-γ triggered chemokine CX3CL1 expression in the vessel lumen, which facilitated continuous crawling of human patrolling and proangiogenic monocytes; it also rendered these monocytes unresponsive to chemokines that are required for their extravasation. Expression of the angiogenic factor vascular endothelial growth factor (VEGF) and the inflammatory cytokine TNF by tumor cells facilitated human patrolling and proangiogenic monocyte extravasation by triggering GATA3-mediated repression of CX3CL1 expression [50]. These studies demonstrated crosstalk between PMo and tumor cells, and suggested NR4A1-mediated mechanistic pathways for future exploration in various cancer types. NR4A1 in Adaptive Immunity to Cancer In addition to the role of NR4A1 in myeloid cell-mediated antitumor immunity, it has also been implicated in adaptive immunity. NR4A NRs constitute crucial transcription factors for maintaining regulatory T cell (Treg) genetic programs and they contribute to Treg-mediated suppression of antitumor immunity in the tumor microenvironment [51–53] (Table 3). For instance, thymic Treg development was completely suppressed in mice lacking all three NR4A factors in T cells (Cd4CreNr4a1fl/flNr4a2fl/flNr4a3−/−), and mice died within 3 weeks after birth because of systemic multiorgan autoimmunity [52]. NR4A factors are highly expressed on mature Foxp3+ Tregs and are necessary for maintaining Treg stability and suppressive activity [53]. They not only regulate Foxp3 expression but also globally regulate the Treg-specific transcriptional program. Thus, NR4A-deficient Tregs showed not only reduced expression of Foxp3 but also global dysregulation of Treg signature genes, including Foxp3-independent genes such as Ikzf4 (Eos). Moreover, selective deletion of Nr4a1/Nr4a2 within Foxp3+ Tregs markedly suppressed tumor growth and induced strong antitumor immune responses [54]. In another study, NR4A1 was found to regulate CD8+ T cell development by recruiting the corepressor, CoREST, to suppress Runx3 expression in CD8+ T cells [55]. In Nr4a1−/− mice, elevated Runx3 expression in thymocytes was observed, causing a twofold increase in the frequency and total number of intrathymic and peripheral CD8+ T cells relative to controls [55]. Moreover, NR4A1 regulated the expansion, differentiation, and function of CD8+ T cells via direct transcriptional repression of Irf4. Indeed, IRF4 regulation was lost in the absence of NR4A1, leading to increased Irf4 expression and, in turn, a faster rate of CD8+ T cell proliferation and expansion. In addition, Nr4a1−/− mice demonstrated elevated CD8+ T cell effector responses with higher clearance capacity of Listeria monocytogenes relative to WT mice [56]. Recently, the role of NR4A1 in tolerant CD4+ T cells has also been investigated. An in vitro T cell tolerance induction system was used in which naive CD25loCD44loCD62LhiCD4+ T cells, purified from OT-II transgenic mice, were activated with OVA in the presence of irradiated B7.1−/−B7.2−/−B7h−/− or WT antigen-presenting cells (APCs) for 4 days; the mice were used to characterize genome-wide epigenetic and gene expression profiles in tolerant T cells, and distinct molecular features were found in effector and regulatory T cells [57]. The transcription factor NR4A1 was stably overexpressed in tolerant

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T cells. In antitumor and antiviral immunity mouse models (e.g., EG.7 tumors, and acute and chronic infections with lymphocytic choriomeningitis virus, respectively), and mouse models with NR4A1 upregulation displayed impaired effector T cell differentiation, whereas ablation of NR4A1 overcame T cell tolerance and augmented effector function relative to WT mice. In addition, NR4A1 upregulation led to reduced transcription of Il2, Ifng, and Tbx21, and increased Cblb and Itch mRNA expression, relative to WT mice; by contrast, Nr4a1 KO enhanced the production of IL-2 and IFN-γ relative to WT mice [57]. NR4A1 was suggested to be preferentially recruited to transcription factor AP-1 binding sites, thereby repressing effector gene expression by suppressing AP-1 function. NR4A1 binding was also reported to enhance histone 3 lysine 27 acetylation (H3K27ac), thus activating tolerance-related genes such as Gata3, Nt5e, Bach2, and Samhd1 relative to controls [57]. These observations suggest that NR4A1 can modulate T cell dysfunction and could be potentially useful as an emerging immunotherapeutic target in malignancies, pending further investigations.

Outstanding Questions

Concluding Remarks

Can we identify novel specific subsets of NR-positive immune cells that modulate immune reactions and regulate cancer hallmarks?

Despite long-term responses, most cancer patients fail to respond to the existing immunotherapies [58]. Given increased recognition of the importance of NRs in cancer inflammation and immunity, ongoing efforts have been made to combine targeting of NR ligands with current immunotherapy regimens. One future direction of research on NRs and cancer immunity will be to screen novel combinations of NR ligands with immunotherapy regimens to achieve maximized therapeutic efficacy for cancer patients. In addition, given the evolution of next-generation sequencing technologies, together with genome-wide functional screening pipelines, it may be increasingly possible to identify, based on NR gene expression, relevant immune cell subsets with particular functions in cancer immunity. These subsets of immune cells might be functionally manipulated with specific NR ligands for specific therapeutic purposes. Moreover, the identification of newer generations of NR agonists, antagonists, and modulators with improved therapeutic efficacy, optimized tissue specificity, and minimized side effects might provide more effective options for the combinatorial use of NR targeting with immunotherapeutic strategies in cancer patients [59]. The immunomodulatory traits of these new compounds also await further exploration to optimize their clinical indications. However, many open questions remain (see Outstanding Questions). Collectively, as the role of NRs in cancer inflammation and immunity has revolutionized cancer treatment strategies in the past, further understanding of these important factors might continue to provide novel horizons in the future development of cancer therapeutics. Acknowledgments We thank Dr Ryan C. Gimple from the Department of Medicine, Division of Regenerative Medicine, University of California San Diego, USA for polishing the language of this manuscript. This work was supported by grants from the National Natural Science Foundation of China (81822034, 81821002, 81773119, 81402396, 91740111, and 81871232), the National Key Research and Development Program of China (2017YFA0106800, 2018YFA0109200, and 2016YFA0502203), the Sichuan Science-Technology International Cooperation Project (grant 2019YFH0144), and Direct Scientific Research Grants from West China Second Hospital, Sichuan University (grants KS021 and K1907). J.A.G. is thankful to the Robert A. Welch Foundation for a grant (E-0004), the Brockman Foundation, the Swedish Cancer Foundation, the Center for Innovative Medicine, and the Novo Nordisk Fund.

Resources i

https://clinicaltrials.gov/ct2/show/NCT02922764

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Although several NRs are involved in oncogenic virus infections and ultimately in tumor development and progression, do any other NRs and signaling cascades also participate in this process? The gut microbiota has been implicated in tumorigenesis and can impact on cancer patient responses to treatment. Can we further investigate the underlying molecular mechanisms involving NRs in the crosstalk between gut microbiota and the host in terms of tumorigenesis and modulation of treatment responses?

How can we identify novel NR ligands/ modulators with optimized therapeutic efficacy, improved safety profiles, and enhanced tissue specificity for cancer treatments, to partially modulate inflammatory responses or immune reactions? Can clinicians and researchers closely cooperate to launch cancer clinical trials that specifically investigate the therapeutic efficacy of NR-based immune checkpoint blockade therapy or combined regimens of NR ligands/ modulators with established immune checkpoint blockade?

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