In the last decade, the survival rate of cancer patients has significantly improved caused by advances in cancer therapies. However, some effective anticancer drugs, such as anthracyclines, also exert detrimental effects on the heart causing progressive and irreversible heart failure, which negatively impact the quality of life and prognosis of patients. Several alterations have been identified in cardiomyocytes to explain the cardiotoxic effects of anthracyclines, such as doxorubicin (Dox). More recently, cardio-oncology research has focused on other cardiac cells, including endothelial cells, fibroblasts, and immune cells, because Dox alters their functional crosstalk, preventing the maintenance of proper cardiovascular homeostasis and function. 1 Therefore, understanding the effects of Dox in disrupting these interactions is essential for exploring novel therapeutic strategies that can reduce cardiotoxicity preserving the effectiveness of cancer treatments.
Recent research has highlighted the involvement of macrophages in doxorubicin-induced cardiomyopathy (DiCM) suggesting distinct roles for the different macrophage subtypes. 1 , 2 , 3 Cardiac resident macrophages serve as critical immune modulators in DiCM. They are sensitive to Dox, and the surviving ones are induced to proliferate through the activation of the SR-A1-c-Myc axis antagonizing the progression of DiCM. Indeed, they have an anti-inflammatory phenotype and contribute to cardiac repair. 3 Accordingly, the injection of M2b macrophages in DiCM models exerts cardioprotective effects by promoting cardiac autophagy. 4 In contrast, monocyte-derived macrophages infiltrate the heart in response to Dox and early exhibit a proinflammatory phenotype that impairs cardiac function. 2 The infiltrating macrophages release catecholamines activating cardiac βARs in cardiomyocytes and inducing p53-dependent mitochondrial damage and cell death. 2 This evidence highlights a crosstalk between macrophages and cardiomyocytes that precedes cardiac dysfunction suggesting that macrophage-secreted factors significantly contribute to cardiac cell damage, beyond the direct effect of Dox. These findings suggest that strategies aimed to modulate macrophage polarization (M1 vs M2) or inhibit their recruitment could prevent heart damage.
In this issue of JACC: Basic to Translational Science , the publication by Liu et al 5 supports the proof of concept that macrophages actively participate in DiCM and extends the knowledge of the involved molecular mechanisms, suggesting the macrophage-associated membrane protein SLAMF7 as a key regulator of inflammatory responses. In a mouse model of cardiotoxicity, the authors show that Dox reduces cardiac expression of SLAMF7, suggesting its potential protective role in failing hearts. Interestingly, Dox also induces a significant reduction in SLAMF6 expression, while increasing SLAMF1 expression in cardiac tissues 5 suggesting their potential involvement in DiCM. Their role is not further investigated in this study, but it would be interesting to explore whether SLAMF subtypes interact with each other in response to Dox. In vivo experiments in this study were carried out in mouse models with systemic (SLAMF7 KO) and macrophage-specific knock-out of SLAMF7 (SLAMF7 MCKO ). 5 In SLAMF7 KO mice, Dox reduced heart weight, cardiac dimensions, and cardiomyocyte cross-sectional area and increased interstitial fibrosis and reactive oxygen species levels, highlighting an amplification of cardiotoxic effects compared with control mice. Similarly, the macrophage-specific deletion of SLAMF7 in mice worsened systolic dysfunction induced by Dox, as indicated by reduced left ventricular ejection fraction and fractional shortening as well as elevated levels of cardiac markers of dysfunction (cardiac troponin T and creatine kinase-MB). In these mice, a shift in macrophage polarization toward the M1 phenotype leads to a significant increase in the release of proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, and IL-6). These effects are reverted by recombinant SLAMF7 protein (rSLAMF7) that induces a significant improvement in survival rates of mice, an amelioration of cardiac function, and a reduction of inflammation. Thus, this study demonstrates that SLAMF7 modulates macrophage-mediated cardiac inflammation supporting the proof of concept that inflammation is strongly involved in the development of cardiotoxicity and paving the way for novel potential therapeutic strategies. At the molecular level, Liu et al 5 show that SLAM7 interacts with and inhibits TRAF6 in macrophages in response to inflammatory stimuli, and TRAF6 inhibition, in turn, reduces nuclear factor kappa B (NFκB) protein expression and proinflammatory cytokine release suggesting that TRAF6/NFκB axis is a downstream target of SLAMF7 in DiCM. SLAMF7 signaling in this study is not enough investigated, also considering that the role of SLAMF7/TRAF6/ NFκB axis is already described in macrophages in a different pathologic context. 6 Additional studies are warranted to better define SLAMF7 signaling in macrophages in response to Dox and identify its targets and other potential mechanisms that are involved in its regulation.
In this study, the role of macrophages in DiCM and their involvement in cardiac inflammation is evaluated in male mice, but gender differences should be taken into account because women seem to be more susceptible to DiCM than men. 7 Therefore, evaluating the role of SLAMF7 in female mouse models of DiCM could provide a more comprehensive understanding of sex-based differences in cardiotoxicity and responses to treatments.
Overall, the findings from Liu et al 5 propose SLAMF7 activation in macrophages as a potential approach to counteract inflammatory responses that contribute to the development of DiCM. However, it should be considered that SLAMF7 is an important regulatory molecule on the surface of some immune cells whose signaling is highly complex, and protein expression and phenotype vary depending on cell type. SLAMF7 is highly expressed in myeloma cells playing an important role in the pathogenesis of multiple myeloma, and recent studies also suggest its involvement in the progression of breast cancer and several immune cell-related diseases. 8 Monoclonal antibodies targeting SLAMF7 have been developed to treat multiple myeloma by inducing NK cell-mediated cytotoxicity in cancer cells, but this ability could be inhibited by recombinant SLAMF7 protein. Although SLAMF7 activation could represent a promising strategy to mitigate cardiotoxicity, this approach might interfere with tumor growth, highlighting the need for targeted and selective therapeutic approaches to overcome this potential risk. Also, a moderate expression of SLAMF7 in CD45 + F4/80 - cells is detected, 5 suggesting that also other immune cell compartments could be involved in orchestrating SLAMF7 signaling in response to Dox. Therefore, further investigations are essential to better understand the complexity of SLAMF7 signaling in different contexts and its potential application as a therapeutic target to reduce cardiotoxicity without affecting the effectiveness of cancer treatments.
An alternative approach for targeting macrophage-dependent cardiac damage in response to Dox could be the targeting of their secreted molecules, including catecholamines, 2 inflammatory cytokines, 5 and miRNA 9 ( Figure 1 ), as well as the use of specific NFκB inhibitors. Figure 1 Effects and Targeting of Macrophage-Secreted Molecules in Doxorubicin-Induced Cardiomyopathy SLAMF7 = signaling lymphocytic activation molecule family member 7; TRAF6 = TNF receptor associated factor 6; NFkB = nuclear factor kappa-light-chain-enhancer of activated B cells; IL1-R = Interleukin-1 receptor; p53 = tumor protein p53.
Dox-activated macrophages release catecholamines that affect cardiac cells, and this effect is counteracted by the inhibition of β-adrenergic signaling in cardiomyocytes. 2 Therefore, low doses of β-blockers could prevent the development of DiCM in patients at high cardiovascular risk who are undergoing anthracycline therapy.
Targeting inflammatory cytokines represents another promising strategy to counteract DiCM, as suggested by Liu et al, 5 especially considering the success of monoclonal antibodies targeting IL-1β in reducing hospitalizations for heart failure in at-risk patients. 10 This approach has never been investigated in DiCM; therefore, it would be interesting to explore its potential application.
Some circulating miRNAs, which are released by macrophages in response to Dox, have been identified in a mouse model of cardiotoxicity, 9 suggesting that macrophages may mediate indirect damage to cardiomyocytes via miRNA release. However, the specific effects of these miRNAs on cardiac cells remain to be elucidated.
These macrophage-secreted molecules are promising not only for therapeutic approaches but also for diagnostics, because they could serve as effective biomarkers of cardiotoxicity to identify patients at high risk for DiCM.
Besides macrophages, other immune cell types may also play important roles in modulating cardiac injury and inflammation. Thus, it is essential to explore the contributions of other immune cells in DiCM to increase the knowledge of the molecular mechanisms that cause cardiac damage and identify novel therapeutic approaches.
Funding support and author disclosures
Dr Avvisato has received research grant by the CardioPath program from Federico II University of Naples, Italy. Dr Fiordelisi is supported by agreement between CEINGE-Biotecnologie Avanzate Franco Salvatore S.C. a R.L. and Federico II University of Naples. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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