Abstract
The inducible enzyme heme oxygenase 1 (HO-1) plays a pivotal role in cell defense against different kind of stressors, from oxidative stress to hypoxia. For this reason, HO-1 overexpression has been correlated to cancer aggressiveness in different tumors, being one of the molecular mechanisms used by tumor cells to become resistant to therapies. In addition, HO-1 has a well-recognized role in restraining immune response and in maintaining tolerance. In this context, the possibility that HO-1 induction in immune cells can reduce immune response to cancer and impair cancer immune therapy becomes a hot topic in cancer research. In this review, the most recent evidence pointing out the role of HO-1 in generating a permissive tumor microenvironment has been discussed as well as the most promising therapeutic approaches to increase effectiveness of immune therapies.
Introduction
The enzyme heme oxygenase (HO), described in two different isoforms (HO-1 and HO-2) in mammals, degrades heme group into biliverdin, carbon monoxide (CO), and free iron. The reaction is carried out in presence of molecular oxygen (O2) and nicotinamide adenine dinucleotide phosphate (Maines 1988). HO-1 and HO-2 are codified by two different genes; HMOX1 gene maps on the human chromosome 22q12.3 (Kutty et al. 1994), on a region of approximately 13,148 bp, containing five exons and four introns, and codifies for a 32 kD protein (Waza et al. 2018). HMOX2 gene maps on the human chromosome 16p13.3 and encodes for two protein transcripts of 36 kDa. The degree of similarity between HO-1 and HO-2 is about 50% (McCoubrey & Maines 1994). While HO-2 is constitutively expressed in particular in brain and testis, HO-1 is expressed at very low levels under physiological conditions in the most cell types and upregulated (Waza et al. 2018) as part of stress response mechanisms (Keyse & Tyrrell 1989, Nitti et al. 2022, Sies et al. 2022). Indeed, HO-1 is induced in response to various stressors (e.g. oxidative insults or iron overload) in order to maintain redox homeostasis preventing cell damage or transformation, and the products of its enzymatic activity exert the antioxidant and pro-surviving properties of HO-1. Indeed, biliverdin, together with bilirubin derived by the reduction carried out by biliverdin reductase, as well as CO are potent antioxidant and antiapoptotic molecules. Furthermore, the release of free iron is normally quenched by ferritin, which is synthesized in parallel with HO-1, or extruded by cells through ferroportin (Yanatori et al. 2020), thus preventing Fenton reaction and cell damage.
It is important to note that HO-1 is considered a key molecule in promoting immune tolerance and immune suppression, acting as major regulator of crosstalk between innate and adaptive immune response (Ozen et al. 2015). For instance, it has been well demonstrated that HO-1 induction protects cells and tissues from immunological destruction, promoting the generation of CD4+CD25+ regulatory T cells in mouse models of transplantation (Yamashita et al. 2006).
One of the main effectors of the anti-inflammatory and immunomodulatory action of HO-1 is CO, as demonstrated in different experimental models in which CO administration mimics the effects of HO-1 induction. HO-1-derived CO increases interleukin-10 (IL-10) production from macrophage (Otterbein et al. 2000) and drives maturation and proliferation of T cells toward anti-inflammatory and immunosuppressive phenotype (Song et al. 2004). Moreover, HO-1 induction and CO generation act as a safeguard mechanism to prevent inappropriate T cell activation, as demonstrated in monocyte and in naïve CD4+ and CD8+ T cells (Burt et al. 2010). In addition, CO is able to inhibit antigen presenting cells (APC) maturation and induces Treg proliferation and expansion, ensuring a tolerogenic phenotype (Wegiel et al. 2013). Indeed, both in rats and in human, the overexpression of HO-1 increases the refractory of dendritic cells (DCs) to lipopolysaccharide (LPS)-induced maturation (Chauveau et al. 2005) and limits antigen presentation, thus impairing the activation of CD4+ T-cell responses (Campbell et al. 2018). In addition, HO-1-derived CO promotes immunotolerance at fetal–maternal interface (Sollwedel et al. 2005) and maintains maternal DCs in an immature state, leading to the expansion of the peripheral Treg population (Schumacher et al. 2012, Solano et al. 2015). Furthermore, HO-1 upregulation is involved in the early expansion, differentiation, and maturation of myeloid cells into macrophages (Wegiel et al. 2014). HO-1 overexpression was demonstrated to be responsible for the switch to M2 macrophage polarization, and M2 macrophages showed high levels of HO-1 expression (Naito et al. 2014). Also, HO-1/CO system inhibits both caspase-1 activation and secretion of pro-inflammatory cytokines IL-1β and IL-18, acting as inflammasome inhibitors (Kim & Lee 2013).
However, the anti-inflammatory activity of HO-1 is mediated not only by CO but also by bilirubin. Indeed, the potent anti-inflammatory activity of bilirubin is well recognized since the pioneering observation of Philip S Hench concerning the anti-inflammatory effect of jaundice (Hench 1938). Nowadays, the increased blood levels of bilirubin, when limited to modest increments, are considered protective against cardiovascular diseases, aging, and inflammatory diseases, as widely revised by Vitek and Tiribelli (Vitek et al. 2023). In addition, HO-1-derived bilirubin can act as potent immune modulator also in local tissue microenvironment, for instance favoring wound healing or regulating acute inflammation (Nitti et al. 2020). Indeed, not only bilirubin is able to affect innate immunity by interfering with the complement cascade activation (Basiglio et al. 2007) and inducing M2-macrophages polarization (Zhao et al. 2021) but is also able to affect adaptive immunity. It has been demonstrated that bilirubin inhibits T-cell proliferation and decreases the production of pro-inflammatory Th1 cytokines IL-2 and interferon-γ (IFNγ) in a dose-dependent manner in experimental model of experimental autoimmune encephalomyelitis (EAE) (Liu et al. 2008). In addition, macrophage exposure to bilirubin reduces PD-L1 expression and leads to the expansion of Treg cells (Rocuts et al. 2010, Adin et al. 2017). Furthermore, both in vitro and in vivo bilirubin inhibits the production of inflammatory cytokines such as IL-6 and tumor necrosis factor α (TNFα) and reduces leukocyte transmigration via interaction with endothelial adhesion molecules (Keshavan et al. 2005), in particular decreasing the expression of P- and E-selectin, VCAM, and ICAM (Mazzone et al. 2009, Grochot-Przeczek et al. 2012).
HO-1 anti-inflammatory activity is widely recognized, and HO-1 has been proposed as a potential pharmacological target to treat chronic inflammatory diseases, as recently revised (Campbell et al. 2021).
Thus, due to the prominent role in cell survival and adaptation to stress, the induction of HO-1 in cancer cells can favor tumor progression and resistance to therapy. Nonetheless, in the last years, HO-1 overexpression ha been demonstrated also in cells of the tumor microenvironment (TME) and proved to be involved in the gain of a tolerogenic phenotype.
In this review, the main aspects of the role of HO-1 in the modification of TME and in immune escape will be detailed, highlighting new potential therapeutic approaches in cancer treatment.
Molecular mechanisms of HMOX-1 transcription in cancer cells and in immune cells
HMOX1 gene promoter contains NRF2, hypoxia inducible factor-1 (HIF-1), Sp1, AP-1, nuclear factor-kappa B (NF-kB), and STAT3-binding sites that enable gene transcription in response to oxidative and electrophilic stressors or hypoxia (Lavrovsky et al. 1994, Siow et al. 1999, Prawan et al. 2005, Alam & Cook 2007) and to different signal transduction pathways, setting up a pivotal mechanisms of cell survival and adaptation. Here, we focus on the main molecular mechanisms involved in HMOX1 transcription demonstrated in cancer cells and in immune cells, especially with regard to cancer-immune recognition (Fig. 1).
Schematic representation of the main molecular pathways involved in HMOX1 gene transcription, particularly relevant in cancer cells (blue) and immune cells (purple) or in both (degrading). See text for more details. Image created with BioRender.com.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-23-0006
HO-1 induction in response to the most oxidative and electrophilic stressors mainly relays on the activation of NRF2 (Loboda et al. 2016, Yamamoto et al. 2018), and the role played in cancer progression by NRF2-dependent HO-1 induction is well known and characterized (Shibata et al. 2008, Na & Surh 2014, Furfaro et al. 2016b). NRF2 in the cytosol is bound to its inhibitor Kelch-like ECH-associated protein 1 (KEAP1) which belongs to the Cullin3 (CUL3)-based ubiquitin 3 ligase complex and targets NRF2 to proteasome degradation. Keap1 modifications due to cysteine oxidation or electrophile binding allow NRF2 to move into the nucleus and bind antioxidant/electrophile response elements (AREs) by dimerizing with small MAF proteins, leading to HO-1 transcription (Kobayashi & Yamamoto 2005, Hirotsu et al. 2012).
In cancer cells, NRF2/KEAP1 system can be affected by genetic modifications (Mitsuishi et al. 2012, Furfaro et al. 2016b). Its constitutive activation due to gain-of-function mutations of NRF2 or loss-of-function mutations of KEAP1 has been identified in different kinds of tumors, including head and neck, lung, esophageal, gastric, liver, bladder, and colorectal cancer (Na & Surh 2014). In addition, epigenetic modifications, such as TET-dependent demethylation of NRF2 promoter, or CUL3 hypermethylation of KEAP1, can induce NRF2 constitutive activation in lung, ovarian, and colorectal cancers (Hanada et al. 2012, van der Wijst et al. 2014, Zhao et al. 2015). Recent evidence underlines that NRF2/HO-1 pathways activation works as an oncogenic route that favors murine breast cancer progression modulating immune response in pro-carcinogenic direction (Li et al. 2021).
In immune cells, NRF2-dependent HO-1 induction has a prominent role in macrophage polarization. It has been recently demonstrated that in diet-induced obese (DIO) mice JWH-133, an agonist of cannabinoid receptor 2 (CB2R), regulates its anti-inflammatory and anti-obesity activity by promoting macrophage polarization to M2 in adipose tissue via NRF2/HO-1 pathways (Wu et al. 2020). In addition, the activation of NRF2/HO-1 pathway is linked to IL-10 production and to the gain of a pro-fibrotic feature in macrophages, cooperating with the arhyl hydrocarbon receptor in response to the exposure to uremic toxins (Barisione et al. 2016). Furthermore, NRF2/HO-1 activation in tumor-associated macrophages (TAMs) reduces the efficacy of anticancer treatment and favors melanoma progression, as better discussed in the next sections (Consonni et al. 2021).
HO-1 induction is also observed as a response to the increased intracellular concentration of heme groups (Ogawa et al. 2001). The BTB domain and CNC homolog 1 (Bach1) is a heme-binding protein able to bind ARE sequences repressing HMOX1 transcription (Kikuchi et al. 2005, Ryter & Choi 2005, Chapple et al. 2016, Piras et al. 2017, Zhang et al. 2019). Heme groups can bind Bach1 that in turns detaches from ARE sequences enabling HMOX1 transcription (Ogawa et al. 2001, Davudian et al. 2016, Nitti et al. 2017). The degradation of heme due to the activity of HO-1 stabilizes Bach1 and prevents its further degradation, restoring its level. Thus, when Bach1 levels are restored, HO-1 levels in turns decreases. In cancer cells, this mutual regulation between HO-1 and BACH1 seems lost. Indeed, BACH1 stabilization can be observed in the presence of HO-1 expression in lung cancer metastasis and correlates with poor prognosis (Lignitto et al. 2019, Wiel et al. 2019). The role of heme in BACH1 modification and the correlation with tumor progression has been demonstrated and reviewed elsewhere (Muhseena et al. 2021). Considering immune cells, it has been recently well proved that HO-1 can be induced by heme independently by NRF2 but dependently by BACH1, at least in peritoneal macrophages (Zhang et al. 2021), and this aspect seems to be particularly relevant in inflammatory response. Moreover, the possibility to induce HO-1 in a Bach1-dependent but NRF2-independent way has been demonstrated for cannabidiol and proved to exert anti-inflammatory effects (Casares et al. 2020).
The different kinases (i.e. MAPKs and PI3K/AKT) involved in HO-1 induction in cancer cells can act on NRF2 but also on other transcription factors. In MCF-7 breast cancer cells treated with cadmium chloride, the induction of HO-1 is due to p38 MAPK-dependent NRF2 activation (Alam et al. 2000). In human gastric cancers, HO-1 induction is mediated by ERK activation but independent of NRF2 (Liu et al. 2004). Also, PI3K/AKT plays a role in HO-1 induction in neuroblastoma and in cholangiocarcinoma treated with guanosine (Dal-Cim et al. 2012) or piperlongumine (Talabnin et al. 2020), respectively.
HIF-1α (Wang et al. 1995, Pugh et al. 1997) also induces HO-1 expression in response to cellular stressors, including endogenous ROS and oxygen deprivation (Chin et al. 2007, Palazon et al. 2014). A specific HIF-1α/HO-1 pathway has been well characterized in halting inflammatory response in lungs (Hu et al. 2015) and correlated to the modulation of mitochondrial biogenesis (Yu et al. 2016, Shi et al. 2021). Importantly, a specific role of HIF-1α-dependent HO-1 induction has been demonstrated to be involved in maintaining Hodgkin lymphoma cells as undifferentiated (Nakashima et al. 2021). Notably, the expression of HIF-1α has been proved to be highly interconnected with HO-1 overexpression in order to constitute a highly tolerogenic TME, favoring M2 polarization and Treg recruitment in breast cancer (Duechler et al. 2014).
Sp1 and AP-1 have been demonstrated to be responsible of HO-1 induction in mouse brain endothelial cells exposed to prostaglandin 15d-PGJ2 downstream the activation of ROS/PKCδ/JNK1/2 cascade (Yang et al. 2022). Moreover, it has been demonstrated that HO-1 is induced through the activation of AP-1 via PKCα/Pyk2/p38α MAPK- or JNK1/2-dependent c-Jun activation, in human pulmonary alveolar cells exposed to mevastatin, and suppresses TNFα-dependent inflammation (Yang et al. 2020).
In addition, the relevance of AP-1 and NF-kB in the regulation of HMOX1 transcription has been described in the inflammatory response (Luu Hoang et al. 2021). Indeed, the binding site for NF-kB in the promoter region of HO-1 was identified by Abraham’s lab in 1996 (Lavrovsky et al. 1994) and confirmed later on as part of the mechanisms underlying HO-1 expression in macrophages exposed to LPS (Kurata et al. 1996) or in epithelial cells treated with TGFβ (Lin et al. 2007a). Interestingly, also the pharmacological modulation of this pathway has been proposed in the treatment of B-cell lymphoma (Huang et al. 2016).
With particular relevance to macrophages, IL-10 induces the upregulation of HO-1 via IL-10R, through STAT3 phosphorylation and its binding to the STAT-binding element (SBE) in the promoter region of HO-1 (Ricchetti et al. 2004, Naito et al. 2014). Notably, STAT3 can also be activated downstream of HO-1 induction, as HO-1 inhibition was able to downregulate STAT3 activation (Magri et al. 2022).
It is important to note that the presence of two kinds of polymorphisms such as (GT)n repeats and SNPs in gene promoter can influence HMOX1 inducibility. Indeed, the length of (GT)n repeats (long vs short) correlates with different transcriptional activity (lower vs higher, respectively) and with the development of cardiovascular and pulmonary diseases (Exner et al. 2004, Daenen et al. 2016). Also, a higher degree of inducibility is associated with SNP413 A>T and with a reduction of cardiovascular disease risk (Ono et al. 2004). Yet, few data have been provided so far as far as neoplastic pathology is concerned, as previously reported by us (Nitti et al. 2021).
HO-1 expression is regulated by microRNA as well, as elsewhere revised (Cheng et al. 2013), directly or through the modulation of NRF2-dependent activation pathway affecting cancer progression. Indeed, the modulation of NRF2/HO-1 by miRNA-155 or miR200a has a role in lung cancer and breast cancer progression, respectively (Eades et al. 2011, Gu et al. 2017). Also, miR-1254 or miR-193a-5p acts directly on HO-1 and reduces the growth of non-small cell lung cancer (NSCLC) and prostate cancer, respectively (Pu et al. 2017, Yang et al. 2017), and we proved that miR494 favors neuroblastoma cell survival in oxidative stress condition by inducing HO-1 (Piras et al. 2018).
HO-1 protein structure and localization
HO-1 has an α-helical structure. The heme group is coordinated with His 25 and is accommodated between the distal and the proximal helices generating a closer conformation in the holoenzyme (Rahman et al. 2013).
HO-1 is mainly localated in the endoplasmic reticulum (ER) where it co-localizes with cytochrome P450 (CYP450) reductase (Durante 2020), but evidence has been provided also for plasma membrane, where HO-1 co-localizes with caveolin 1 and 2 (Jung et al. 2003), mitochondria (Slebos et al. 2007), and nuclei (Lin et al. 2007b). It has been proved that HO-1 prevents apoptosis acting on caveolin 1 through the activity of CO (Kim et al. 2005). Localization at the mitochondria seems to be involved in the control of apoptotic pathway, in a mutual relation with HO-2 (Turkseven et al. 2007). In addition, mitochondrial HO-1 controls the metabolism of heme groups (Converso et al. 2006). However, the role played by the different localization of HO-1 in the progression of tumors has not been evaluated, with the exception of the nuclear localization. Indeed, a truncated form of HO-1, with nuclear localization and no enzymatic activity, derived by proteolytic activity of signal peptide peptidase (SSP), has been described (Lin et al. 2007b, Hsu et al. 2015). Being characterized by a transcriptional activity, truncated HO-1 has been hypothesized to be importantly involved in cancer progression. In the acetylated form, truncated HO-1 increases AP-1 transcriptional activity, leading to cancer progression (Hsu et al. 2017, Mascaró et al. 2021). Contrasting results have been described, both highlighting the association between nuclear compartmentalization and disease severity in chronic myeloid leukemia (CML) (Tibullo et al. 2013) and providing opposite observations (Ferrando et al. 2011, Degese et al. 2012), and the topic has been revised in deep elsewhere (Mascaró et al. 2021).
To note, HO-1 has been detected extracellularly, in plasma, serum, milk, cerebrovascular fluids, and urine (Serpero et al. 2012, Signorelli et al. 2016, Vanella et al. 2016), opening to the chance to investigate a potential role of HO-1 as biomarker (Tibullo et al. 2013). The mechanisms underlying the extracellular localization are still largely unknown, and both the active secretion and the result of cellular lysis have been hypothesized. In patients with acute myocardial infarction, the plasma level of HO-1 does not correlate with biomarkers of necrosis (Novo et al. 2011), and in patients with acute kidney injury, the urinary level of HO-1 mirrors the increased level in renal tissue, as a response to cell damage (Zager et al. 2012). Interestingly, a correlation between the serum level of HO-1 and the progression of abdominal aortic aneurysm has been highlighted (Hofmann et al. 2021). With regard to cancer, it is to note that HO-1 protein is found in the culture medium of breast, lung, melanoma, and kidney tumor cells in the extracellular vesicles (Hurwitz et al. 2016). In this context, HO-1 needs to be taken into consideration as a potential circulating biomarker, especially considering the evident correlation among HO-1 expression levels in cancer tissues and clinical disease score or prognosis, as already reviewed (Nitti et al. 2021), even though more investigations are needed.
HO-1 expression and immune escape
During the progression of neoplastic disease, the upregulation of HO-1 can modify TME, decreasing cancer cell immune recognition. This effect can be achieved by different mechanisms. On one hand, cancer cells can upregulate HO-1 and elude immune surveillance modifying the expression of receptors for immune cells or through the generation of immune-suppressive cytokines. On the other hand, immune cells themselves can overexpress HO-1 gaining a less aggressive, tolerant phenotype. These two main mechanisms are detailed below.
HO-1 expression in cancer cells reduces immune recognition
The induction of HO-1 in cancer cells has been related to the progression of disease, and associated with resistance to therapy, invasiveness, metastasis, and angiogenesis, as widely reviewed by us and others (Jozkowicz et al. 2007, Was et al. 2010, Nitti et al. 2017) and not further discussed here.
Nonetheless, in the last years, HO-1 upregulation in cancer cells gained attention for the ability to impair immune recognition (Fig. 2).
Schematic representation of the immune-suppressive activity induced by HO-1 overexpression in cancer cells, in TAMs, and in DCs and the effects on T and NK cells that lead to immune-escape and cancer progression. Image created with BioRender.com.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-23-0006
We have recently demonstrated that, in BRAFV600-mutated melanoma cells treated with vemurafenib (PLX4032), HO-1 overexpression reduces natural killer (NK) recognition impairing the expression of NK ligands (B7-H6 and ULBP3), both under standard culture conditions (Furfaro et al. 2020) and under physiological oxygen tension or hypoxia (Furfaro et al. 2022). Moreover, the induction of HO-1 in cervical cancer cells reduces the expression of specific markers of NK activation (NKG2D, NKp30, and NKp46) and the production of IFNγ and TNFα in a co-culture model (Gomez-Lomeli et al. 2014). In both experimental systems, the downregulation or the enzymatic inhibition of HO-1 in cancer cells restores the NK antitumor activity restoring the expression of NK ligands on cancer cells (Furfaro et al. 2020, 2022) or NK-activating receptors (Gomez-Lomeli et al. 2014). In line with these results, HO-1 overexpression in acute myeloid leukemia (AML) cells has been shown to decrease NK cytotoxicity activity by inhibiting CD48-2B4 axis both in vitro and in vivo and is associated with a poor prognosis in term of overall survival, refractory, and relapse (Zhang et al. 2022). More recently, the induction of HO-1 in AML has been proved to reduce the expression of HLA-C, thus favoring tumor escape from NK-mediated killing (Feng et al. 2023).
Furthermore, breast cancer and melanoma progression has been successfully halted by fasting-mimicking diet that increases the infiltration of cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) through the downregulation of HO-1 in cancer cells (Di Biase & Longo 2016).
Interestingly, a potent immune-suppressive response is observed in regulatory CD8+ T cells that specifically recognized HO-1 and that crucially contribute to the suppression of T-mediated antitumoral response (Andersen et al. 2009). Thus, HO-1 could drive the suppression of T-cell response once recognized by immune cells. In addition, these cells have been detected not only in tumor mass but also in peripheral blood potentially working as biomarkers in cancer patients (Andersen et al. 2009).
HO-1 expression in TAMs, TILs, and DCs impairs cancer immune recognition
In recent years, HO-1 upregulation has been described in immune cells of TME, where it plays a role in suppressing antitumor response promoting a permissive environment for growth and metastasis. In this context, the most important evidence comes from the analysis of TAMs, TILs, and DCs (Luu Hoang et al. 2021).
TAMs are the main source of HO-1 in the TME. They respond to different tumor-derived stimuli and are able to differentiate and reprogram into different subsets that are beyond the classic M1 and M2 dichotomy, and HO-1 has been recently proved to be overexpressed in different specific subgroups of TAMs (Arnold et al. 2014, Muliaditan et al. 2018a, Consonni et al. 2021).
Indeed, in two murine models of Lewis lung carcinoma and pancreatic ductal adenocarcinoma, a particular subset of HO-1-positive TAMs co-expressing fibroblast activation protein alpha (FAP+HO-1+ TAMs) has been described (Arnold et al. 2014). In these cells, HO-1 conditional ablation or HO-1 pharmacological inhibition decreases tumor growth, confirming the immunosuppressive role of HO-1 in TAMs.
Similar TAM subsets were found in tissue sections of human adenocarcinoma and in the 4T1 orthotopic model of breast adenocarcinoma (Muliaditan et al. 2018a). They are predominantly located in the perivascular region of the tumor and facilitate trans-endothelial migration and metastatic spread, and HO-1 inhibition completely abrogates this effect (Muliaditan et al. 2018a).
Positive staining for HO-1 was also found in CD11b+- and F4/80+-infiltrating macrophages in E.G7-ovalbumin (OVA) tumor-bearing mice (Alaluf et al. 2020). HO-1+ TAMs derive from a subset of Ly6Chi monocytes that gradually differentiate into Ly6CloMHCII+ TAMs in TME. Compared with HO-1-negative TAMs, this subset shows decreased MHC II expression in line to its immunosuppressive feature.
Recently, another particular subgroup of TAMs expressing high levels of HO-1 (F4/80hiCD115hiC3aRhiCD88hi) has been identified (Consonni et al. 2021). This population, phenotypically similar to erythrocyte macrophages, preferentially accumulates at the invasive edge of the tumor, in line with their involvement in neoangiogenesis, epithelial-to-mesenchymal transition, and tumor spread. Furthermore, M-CSF or C3a-induced differentiation of bone marrow-derived monocytes (BMDMs) upregulates HO-1 in an NRF2-dependent way coordinated by the p50NF-kBi-CSF-R1-C3aR axis and induces TAM phenotype in CO-dependent manner. Importantly, both the deletion of myeloid HO-1 and the inhibition of recruitment pathway of HO-1+ TAMs are able to block metastasis formation and to enhance the effect of immunotherapy, in particular increasing the efficacy of anti-PD-1 therapy. Moreover, in patients with stage III melanoma, HO-1 expression levels in the peripheral monocytes correlate with HO-1 expression in CD163+ cells of metastatic lesions, thus highlighting the correlation between HO-1 expression and poor prognosis (Consonni et al. 2021).
Other evidence shows that following chemotherapy-induced phagocytosis of tumor cells, TAMs upregulate HO-1 expression that, in turns, hampers M1 polarization, attenuating the effect of chemotherapeutics. In fact, using HO-1 knockout mice or in the presence of HO-1 inhibitor the response to chemotherapy is efficiently restored (Kim et al. 2020, 2021).
In addition, HO-1 plays a role in the metabolic changes of TAMs, such as modification in aminoacid metabolism, driving the establishment of an immunosuppressive microenvironment (Magri et al. 2022). In fact, the inhibition of HO-1 in BMDMs significantly reduces the expression of IDO-1 and Arg2 (Magri et al. 2022), two essential enzymes involved in the catabolism of l-arginine and l-tryptophane, associated with the immunosuppressive network in cancer (Mondanelli et al. 2017).
Notably, HO-1 expression in TAMs modulates the activity of TILs, DCs, and NK cells toward an immune-suppressive feature. Indeed, the inhibition of HO-1 in TAMs affects the production of cytokines involved in T-cell recruitment and regulation, leading to a reduction in the expression of Tregs and increasing the proportion of CD8+ T cells, highlighting the strategic potential associated with TAMs reprogramming by HO-1 inactivation (Kim et al. 2021). Importantly, myeloid ablation of HO-1 is able to improve the response toward therapeutic immunization promoting antitumor CD8+ T cell proliferation and cytotoxicity (Alaluf et al. 2020).
Moreover, it has recently been shown that in glioblastoma tissues, a large amount of CD68+/HO-1+ macrophages and a lower percentage of CD8+ T lymphocytes are present; HO-1 inhibition, which strongly reduces IL-10 release, is able to drive the complete recovery of T-cell proliferation (Magri et al. 2022).
Furthermore, HO-1 deletion, by promoting a phenotypic switch in F4/80hi TAMs, increases the expression of IFNγ and GrzB in CD8+ T cells, leading to a higher frequency of effector memory cells (CD8+CD44+CD62L– cells) and to an augmented CD8+/CD4+FoxP3+ ratio restoring their antitumor activities (Consonni et al. 2021). Notably, the infiltration of HO-1+CD4+CD25+ FoxP3+ Tregs correlates with the progression and grading of glioma (El Andaloussi & Lesniak 2007).
With regard to DCs, it has been demonstrated that HO-1 induction maintains DCs in an immature and pro-tolerogenic status (Chauveau et al. 2005). Moreover, the immunomodulatory activity of CD4+CD25+ Tregs is dependent on HO-1 expression in DCs (George et al. 2008). Importantly, pro-tolerogenic signature of DCs in TME is achieved in an HO-1-dependent manner (Trojandt et al. 2016).
No evidence of HO-1 upregulation in NK cells in TME has been pointed out so far.
HO-1 inhibitors in cancer therapy
The role of HO-1 in tumor progression appears, then, to be related to two crucial aspects: on one hand, HO-1 exerts an antiapoptotic, pro-surviving activity that protects cancer cells from the death induced by therapeutic agents, and this has been widely revised elsewhere by us and others (Podkalicka et al. 2018, Nitti et al. 2021). However, HO-1 carries out a crucial immune-suppressive activity both in tumor cells, reducing their immune recognition, and in immune cells reducing their antitumoral activity. Thus, the inhibition of HO-1 activity as well as its molecular downregulation reducing the availability of HO-1 bioactive products, CO and bilirubin, can have strategic therapeutic potential acting both as chemosensitizer, increasing the efficacy of traditional anticancer treatments (chemo-, radio-, and photo- dynamic therapies), and as immune-stimulatory tool improving the efficacy of novel immunotherapy approaches, as explained below.
Different pharmacological compounds as well as genetic tools able to downregulate HO-1 activity have been proposed (Podkalicka et al. 2018). Among pharmacological compounds, proto- and mesoporphyrin derivatives and imidazole-based compounds are the most well known (Podkalicka et al. 2018).
The first generation of HO inhibitors are metalloporphyrins (Vreman et al. 1993). They are structurally similar to heme molecules and strongly inhibit HO-1 activity, although they lack in specificity (Schulz et al. 2012). Indeed, they act on other heme-dependent enzymes such as nitric oxide synthase (NOS), soluble guanylate cyclase (sGC), and CYP450 (Appleton et al. 1999, Kinobe et al. 2008). Moreover, their translational applicability was sometimes limited due to their poor solubility in aqueous solutions. However, the generation of water-soluble compounds by conjugation with specific molecules, for example, polyethylene glycol or amphiphilic styrene–maleic acid copolymer, increased their applicability (Sahoo et al. 2002, Iyer et al. 2007, Herrmann et al. 2012).
Metalloporphyrins showed efficacy both in vitro and in vivo. The most used are zinc-protoporphyrin IX (ZnPPIX), tin-protoporphyrin IX (SnPPIX), and tin-mesoporphyrin IX (SnMPIX) (Podkalicka et al. 2018, Nitti et al. 2021).
It has been shown that ZnPPIX treatment enhances the efficacy of cisplatin in hepatoma cancer cells (Liu et al. 2014), increases the apoptotic rate in glioma cells treated with arsenic trioxide (Liu et al. 2011) and is able to enhance the cytotoxic effect of gemcitabine in urothelial cancer cells (Miyake et al. 2010). We have demonstrated that HO-1 inhibition by ZnPPIX sensitizes neuroblastoma cells to glutathione depletion and etoposide (Furfaro et al. 2012) and to bortezomib treatments (Furfaro et al. 2014). Furthermore, in BRAFV600-mutated melanoma cells, SnMPIX increases cell death induced by vemurafenib/PLX4032 (Furfaro et al. 2020).
Moreover, ZnPPIX treatment sensitizes A549 NSCLC cells to radiotherapy (Zhang et al. 2011) and colon and ovarian cancer cells to photodynamic therapy (Nowis et al. 2006), and SnPPIX sensitizes melanoma cells to photodynamic therapy (Frank et al. 2007).
Importantly, it has been recently reported that the inhibition of HO-1 by metalloporphyrins reprograms the immune response toward tumor cells and consequently improves the efficacy of immunotherapy. Indeed, FAP+HO-1+ TAMs can be therapeutically targeted using SnMPIX, which prevents metastatic spread by blocking HO-1-dependent CO release (Muliaditan et al. 2018a). Moreover, the inhibition of HO-1 activity by ZnPPIX restores the expression of pro-inflammatory genes such as TNFα and CXCL10 while downregulating the expression of typical anti-inflammatory genes like IL-10 and CCL22. These effects are reversed by treatment with CO-releasing molecule, CORM-2, confirming the role played by HO-1-dependent CO in suppressing tumor immune recognition (Consonni et al. 2021). In addition, in mice treated with anti-PD-1, HO-1 inhibition with ZnPPIX improves the efficacy of immunotherapy, resulting in a decrease of tumor volume (Consonni et al. 2021). More recently, in macrophage derived from glioblastoma patients, it has been proved that treatments with ZnPPIX or SnPPIX decrease PD-L1 expression; on the contrary, HO-1 induction obtained by macrophage exposure to cobalt protoporphyrin IX (CoPPIX) increases PD-L1 expression, indicating that PD-L1 regulation depends on HO-1 activity (Magri et al. 2022). Also, in a preclinical model of breast cancer, it has been demonstrated that SnMPIX can be used as immune checkpoint; by targeting myeloid-derived HO-1, it improves response to chemotherapy, achieving the efficacy of PD-1 blockade (Muliaditan et al. 2018b).
Furthermore, the inhibition of HO-1 can be a strategy to improve the adoptive immunotherapy. Indeed, SnMPIX-based HO-1 inhibition significantly increases the generation of WT1 leukemia-specific T cells, from healthy donors, enhancing the effective T-cell immunity in leukemia patients (Schillingmann et al. 2019).
The second generation of HO-1 inhibitors, namely the imidazole-based compounds, are water-soluble non-porphyrin molecules. Acting with a non-competitive mechanism, they show a limited inhibitory activity on NOS, sGC, and CYP450 and are selective toward HO-1 (Kinobe et al. 2006, Pittala et al. 2013). Azalanstat was the first imidazole-based compound described (Vlahakis et al. 2005), but other molecules derived from its structural modification have been synthesized and extensively reviewed by the group of Salerno and Pittalà (Salerno et al. 2019). Recently, a novel acetamide-based HO1 inhibitor, with potent antiproliferative activity in U87MG glioma cells, has been discovered (Fallica et al. 2021).
Among imidazole-based compounds, a small molecule OB-24 shows potent inhibition of HO-1 activity. In particular, OB-24 selectively inhibits HO-1 in prostate advanced cancer cells, leading to a significant decrease of cell proliferation in vitro and a reduction of tumor growth and lymph node/lung metastasis in vivo, also showing a potent synergistic activity when combined with taxol (Alaoui-Jamali et al. 2009). In macrophages from glioblastoma patients, OB-24, similar to ZnPPIX and SnMPIX, reduced PD-L1 expression (Magri et al. 2022). Notably, in B16-F0 melanoma-bearing mice, the combination therapy OB-24 plus anti-PD-1 reduces the tumor size compared to monotherapy. The effect seems to be dependent on the inhibition of cytoprotective function of HO-1; the inhibition of HO-1, indeed, renders melanoma cells more susceptible to immune-mediated killing (Khojandi et al. 2021). In addition, the same authors demonstrated that OB-24-dependent HO-1 inhibition counteracts immune CD4+ and CD8+ TIL evasion of B16 melanoma cells, leading to a decrease in tumor volume. In fact, HO-1 induction by hemin treatment protects B16 cells from CTL-mediated killing (Kuehm et al. 2021).
Furthermore, different genetic tools such as RNA interference and CRISPR/Cas9 technology have been tested to modulate HO-1 activity in cancer therapy.
Small interfering RNA and short hairpin RNA act by targeting HO-1 at the transcriptional level, leading to a decrease of protein synthesis, and the efficacy of HO-1 silencing in sensitizing cancer cells to therapy has been reported widely. We have demonstrated that HO-1 silencing overcomes cancer cell resistance in neuroblastoma cells exposed to bortezomib (Furfaro et al. 2014, 2016a) and in melanoma cancer cells exposed to target therapy (Furfaro et al. 2020). HO-1 silencing sensitizes pancreatic cancer cell lines to gemcitabine or radiation treatment, leading to a significant inhibition of tumor growth (Berberat et al. 2005). Silencing of HO-1 significantly increased apoptosis as demonstrated in lung (Kim et al. 2008) and colon cancer cells (Busserolles et al. 2006). In the orthotopic model of hepatocellular carcinoma, siHO-1 results in diminished tumor growth (Sass et al. 2008). Moreover, siHO-1 sensitizes human urothelial and cervical cancer cells to 5-aminolevulinic acid-based photodynamic therapy (Miyake et al. 2009, Ohgari et al. 2011) and mediated the photodynamic cytotoxicity, increasing the responsiveness, in C-26 colon adenocarcinoma, in MDAH2774 human ovarian carcinoma (Nowis et al. 2006) and in WM451Lu human metastatic melanoma cells (Frank et al. 2007).
In addition, silencing of HO-1 significantly enhanced the sensitivity of HL-60R AML cell line to chemotherapy (Zhe et al. 2015) and induced apoptosis and cell growth arrest in acute lymphocytic leukemia (Cerny-Reiterer et al. 2014) as well as in chronic lymphocytic leukemia, where the silencing also enhanced the effects of the combined therapy fludarabine plus entinostat (Zhou et al. 2019).
CRISPR/Cas9 editing system through the genetic ablation of HO-1 leads to a stable knockdown and to a high efficiency of protein inhibition. In BRAF-WT melanoma cells, HO-1 CRISPR/Cas9 editing decreased clone formation and tumor cell growth (Liu et al. 2019) and in pancreatic ductal adenocarcinoma suppressed cell proliferation and increased, under hypoxia condition, the efficacy of gemcitabine treatment (Abdalla et al. 2019). Moreover, in T47D breast cancer cells, HO-1 CRISPR/Cas9-mediated knockdown decreased both proliferation and migration and increased cisplatin-induced apoptosis (Evazi Bakhshi et al. 2022).
Importantly, in vivo experimental models on HO-1 ablation leads to important findings on the role played by HO-1 in response to immunotherapy. Indeed, it has been demonstrated that myeloid specific ablation of HO-1 in MN/MCA1 fibrosarcoma enhances the efficacy of anti-PD-1 therapy in decreasing tumor volume and the percentage of metastatic area (Consonni et al. 2021).
In xenograft mouse models of AML, HO-1 gene knockout enhances the antitumor effect of PD-1 inhibition by reducing tumor growth and increasing survival. In this context, HO-1 knockout inhibits the immunosuppressive function of both polymorphonuclear and monocytic/myeloid-derived suppressor cell populations (Zhou et al. 2018). Moreover, it has been demonstrated that HO-1 myeloid ablation strongly improves the response to therapeutic immunization by enhancing antitumor CD8+ T-cell proliferation and cytotoxicity (Alaluf et al. 2020).
The main strategies used for HO-1 inhibition/downregulation are summarized in Table 1.
Efficacy of HO-1 inhibitors in cancer therapies.
Inhibitor | Experimental models | Effect | Reference | |
---|---|---|---|---|
In vitro | In vivo | |||
ZnPPIX | Hepatoma cells (HepG2) | Xenograft mouse model of liver cancer | ZnPPIX enhances cellular sensitivity to cisplatin by increasing ROS production | Liu et al. (2014) |
Human glioma cell lines (U251MG and A172) | ZnPPIX increases cell death and ROS generation in glioma cells potentiating the effects of arsenic trioxide | Liu et al. (2011) | ||
UC lines (T24 and MGHU3) | Xenograft mouse model of urothelial cancer | ZnPPIX sensitizes UC to gemcitabine and irradiation treatment. In in vivo model, ZnPPIX decreases the number of proliferating cells and increases the apoptotic rate. In addition, siHO-1 sensitizes to 5-ALA-based photodynamic therapy |
Miyake et al. (2010) | |
Neuroblastoma cells (GIMEN) | ZnPPIX sensitizes GIMEN cells to GSH depletion and etoposide treatment increasing ROS production | Furfaro et al. (2012) | ||
Neuroblastoma cells (HTLA-230) | ZnPPIX improves the pro-apoptotic effect of proteasome inhibitor-based therapy (bortezomib) in high-risk neuroblastoma cells. HO-1 silencing also sensitizes neuroblastoma cells to bortezomib treatment |
Furfaro et al. (2014) | ||
Human NSCLC cells (A549) | ZnPPIX in combination with irradiation decreases cell viability and clonogenicity and enhances the apoptotic index as well as the percentage of cells in G1 phase. | Zhang et al. (2011) | ||
Human NSCLC cells (A549) | ZnPPIX and siHO-1 increase apoptosis of A549 cells exposed to cisplatin | Kim et al. (2008) | ||
Human ovarian carcinoma cells (MDAH2774) and murine colon adenocarcinoma cells (C-26) | ZnPPIX treatment enhances photodynamic mediated cytotoxicity. HO-1 silencing also sensitizes carcinoma cells to photodymamic therapy |
Nowis et al. (2006) | ||
Mouse 4T1 breast tumor model | Cotreatment with ZnPPIX and paclitaxel decreases tumor growth and restores the proportion of infiltrating CD8+ cytotoxic T lymphocytes | Kim et al. (2020) | ||
Mouse 4T1 breast tumor model | ZnPPIX increases the expression of CD86-M1 polarization marker in mice treated with paclitaxel and decreases the expression of IL-10 in CD11b+ myeloid cells | Kim et al. (2021) | ||
Ex vivo HO-1 deleted TAMs | B-16 melanoma-bearing mice | ZnPPIX treatment decreases tumor growth, improves the effect of anti-PD1 immunotherapy, and reduces the percentage of metastatic area in lung. Myeloid ablation HO-1 also blocks metastasis formation and increases the efficacy of anti PD-1 therapy. Ex vivo deletion of HO-1 in TAMs restores CD8+ T-cell antitumor activity | Consonni et al. (2021) | |
Ex vivo BMDM derived from glioblastoma patients | ZnPPIX treatment decreases PD-L1 expression in macrophages derived from glioblastoma patients and enables the recovery of CD8+ T lymphocytes. Similar results were obtained using OB-24 as HO-1 inhibitor |
Magri et al. (2022) | ||
SnMPIX | Primary BRAFV600 melanoma cells (MeOV-1, MeTA, and MeMi) | SnMPIX increases cell death induced by vemurafenib in BRAFv600-mutated melanoma cells and increases NK cell recognition and killing. siHO-1 also improves the efficacy of vemurafenib, further reducing cell viability and restoring NK ligand expression |
Furfaro et al. (2020) | |
4T1 orthotopic model breast carcinoma | SnMPIX treatment prevents trans-endothelial migration and metastatic dissemination of cancer cells, blocking CO release | Muliaditan et al. (2018a) | ||
Spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT) | SnMPIX targets myeloid HO-1 activity favoring CD8+ T-cell response | Muliaditan et al. (2018b) | ||
Ex vivo PBMC from healthy donors | SnMPIX increases the generation of WT1-specific T cells used in adoptive immunotherapy to improve T-cell-based therapy for leukemia patients | Schillingmann et al. (2019) | ||
OB-24 | Human prostate advance cancer cells (PCA) and resistant cells (PCA-R) | Mouse model of human prostate cancer PC3M | HO-1 inhibition leads to a significant decrease of cell proliferation in vitro and a reduction of tumor growth and lymph-node metastasis in vivo. OB-24 + Taxol shows potent therapeutic effect yielding >90% reduction in tumor growth in vivo. Short hairpin HO-1 shows similar results both in vitro and in vivo. |
Alaoui-Jamali et al. (2009) |
B16-F0 melanoma-bearing mice | Combined therapy OB-24 + anti-PD-1 reduces tumor size compared to monotherapy | Khojandi et al. (2021) | ||
B16-F0 melanoma-bearing mice | HO-1 inhibition counteracts immune CD4+ and CD8+ TIL evasion and leads to a decrease in tumor volume | Kuehm et al. (2021) | ||
siHO-1 | Human pancreatic cancer cells (Panc-1, MIa PaCa-2, SU8686, and Colo 357) | HO-1 silencing sensitizes pancreatic cancer cells to gemcitabine or radiation treatment and leads to a significant decrease in cancer cell growth | Berberat et al. (2005) | |
Colon cancer cells (Caco-2) | HO-1 silencing increases apoptosis | Busserolles et al. (2006) | ||
Human epithelial cervical cancer cells (HeLa) | SnPPIX and HO-1 silencing sensitize to 5-ALA-based photodynamic therapy | Ohgari et al. (2011) | ||
Ex vivo primary ALL cells | HO-1 silencing induces apoptosis and cell growth arrest in cell treated with imatinib. Polyethylene glycol ZnPPIX and styrene maleic acid ZnPPIX also sensitize cells to imatinib | Cerny-Reiterer et al. (2014) | ||
CLL cells | HO-1 silencing enhances the effects of the combined therapy fludarabine plus entinostat | Zhou et al. (2019) | ||
HO-1 CRSPR/Cas9 editing | Melanoma cells (A375) and HO-1 knockout A375 cells | SCID mice injected with A375 cells | HO-1 stable knockdown decreases in vitro clone formation and in vivo tumor growth | Liu et al. (2019) |
Pancreatic ductal adenocarcinoma cell lines (CD18/HPAF, COLO 357, Capan-1, and MIA PaCa-2) | PDAC cell-derived xenograft tumors | HO-1 editing suppresses cell proliferation and increases the efficacy of gemcitabine treatment in hypoxia condition. HO-1 inhibition (ZnPPIX and SnPPIX) suppresses PDAC proliferation, increases susceptibility to gemcitabine, and induces apoptosis under hypoxia |
Abdalla et al. (2019) | |
T47D breast cancer cells | HO-1 editing decreases cell proliferation and migration and increases cisplatin-induced apoptosis | Evazi Bakhshi et al. (2022) | ||
HO-1 ablation | C57/BL6 HO-1 knockout mice injected with HL-60 cells | HO-1 gene knockout enhances the antitumor effect of PD-1 inhibition, leading to a reduction of tumor growth and increasing overall survival | Zhou et al. (2018) | |
Hmox1 ΔM mice | Hmox1 gene deletion in myeloid cells improves the response to therapeutic immunization by enhancing antitumor CD8+T cell proliferation and cytotoxicity | Alaluf et al. (2020) |
5-ALA, 5-aminolevulinic acid; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BMDMs, bone marrow-derived monocytes; GSH, glutathione; NK, natural killer; NSCLC, human non-small cell lung cancer; PBMCs, peripheral blood mononuclear cells; PDAC, pancreatic ductal adenocarcinoma cell; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; ROS, reactive oxygen species; SnMPIX, tin-mesoporphyrin IX; TAMs, tumor-associated macrophages; TILs, tumor-infiltrating lymphocytes; UC, urothelial cells; WT-1, Wilms’ tumor protein 1; ZnPPIX, zinc-protoporphyrin IX.
Conclusions and future perspectives
Although the precise molecular mechanisms involved in the induction of HO-1 in cancer cells and in cells from TME are far from be clearly understood, increasing evidence points out the role played by HO-1 in halting cancer immune recognition. On one hand, the overexpression of HO-1 in tumor cells, as a result of cell adaptation to therapy or to hypoxia, reduces tumor antigenicity; on the other hand, the overexpression of HO-1 in immune cells, in particular TAMs, induces tolerogenic and immune-suppressive phenotype. The two aspects converge toward a common goal, namely favoring tumor progression. Notably, the role of HO-1 in increasing tumor cell resistance to chemo-, radio-, and photodynamic therapies was already recognized, but the role of HO-1 in immune escape opens a new scenario where HO-1 inhibition could efficiently enhance the outcome of immune therapies as well, reducing therapeutic failure or disease relapses.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not for-profit sector.
Author contributor statement
MN, JO, and ALF conceived the study. MN, JO, and ALF wrote the original draft. MN and ALF reviewed the final version. All authors have read and agreed to the published version of the manuscript.
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