Immune Evasion Strategies Research Articles

RNA-seq analysis of murine peyer’s patches at 6 and 18 h post infection with Fasciola hepatica metacecariae

Fasciola hepatica is a zoonotic parasite that not only economically burdens the agribusiness sector, but also infects up to 1 million people worldwide, with no commercial vaccine yet available. An ideal vaccine would induce protection in the gut, curtailing the extensive tissue damage associated with parasite’s migration from the gut to the bile ducts. The design of such a vaccine requires greater knowledge of gut mucosal responses during the early stage of infection. We examined total mRNA expression of the peyer’s patches at 6 and 18 h post F. hepatica infection using RNA sequencing. Differential expression analysis revealed 1341 genes upregulated and 61 genes downregulated at 6 h post infection, while 1562 genes were upregulated and 10 genes downregulated after 18 h. Gene-set enrichment analysis demonstrated that immune specific biological processes were amongst the most downregulated. The Toll-like receptor pathway in particular was significantly affected, the suppression of which is a well-documented immune evasive strategy employed by F. hepatica. In general, the genes identified were associated with suppression of inflammatory responses, helminth induced immune responses and tissue repair/homeostasis. This study provides a rich catalogue of the genes expressed in the early stages of F. hepatica infection, adding to the understanding of early host-parasite interactions and assisting in the design of future studies that look to advance the development of a novel F. hepatica vaccine.

Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype.

Recent preclinical and clinical data suggests enhanced metastatic fitness of hybrid epithelial/mesenchymal (E/M) phenotypes, but mechanistic details regarding their survival strategies during metastasis remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states. We construct and simulate the dynamics of a minimalistic regulatory network encompassing the known associations among regulators of EMT (epithelial-mesenchymal transition) and PD-L1, an established immune-suppressor. Our simulations for the network consisting of SLUG, ZEB1, miR-200, CDH1 and PD-L1, integrated with single-cell and bulk RNA-seq data analysis, elucidate that hybrid E/M cells can have high levels of PD-L1, similar to those seen in cells with a full EMT phenotype, thus obviating the need for cancer cells to undergo a full EMT to be immune-evasive. Specifically, in breast cancer, we show the co-existence of hybrid E/M phenotypes, enhanced resistance to anti-estrogen therapy and increased PD-L1 levels. Our results underscore how the emergent dynamics of interconnected regulatory networks can coordinate different axes of cellular fitness during metastasis.

A short note on predicted motifs in the Thaparocleidus wallagonius genome.

Thaparocleidus wallagonius is a monogenean parasite and a fish-borne pathogen with a worldwide distribution. The genome for Thaparocleidus wallagonius is known. Therefore, it is of interest to report the DNA motif analysis data in the 18S rDNA of Thaparocleidus wallagonius collected from the fish Wallago attu in India. This data forms a framework for an in-depth analysis of the parasite biology and development, immune evasion strategies, virulence and long-term survival within the definitive host.

A functional menadione biosynthesis pathway is required for capsule production by Staphylococcus aureus.

Staphylococcus aureus is a major human pathogen that utilises a wide array of pathogenic and immune evasion strategies to cause disease. One immune evasion strategy, common to many bacterial pathogens, is the ability of S. aureus to produce a capsule that protects the bacteria from several aspects of the human immune system. To identify novel regulators of capsule production by S. aureus, we applied a genome wide association study (GWAS) to a collection of 300 bacteraemia isolates that represent the two major MRSA clones in UK and Irish hospitals: CC22 and CC30. One of the loci associated with capsule production, the menD gene, encodes an enzyme critical to the biosynthesis of menadione. Mutations in this gene that result in menadione auxotrophy induce the slow growing small-colony variant (SCV) form of S. aureus often associated with chronic infections due to their increased resistance to antibiotics and ability to survive inside phagocytes. Utilising such an SCV, we functionally verified this association between menD and capsule production. Although the clinical isolates with polymorphisms in the menD gene in our collections had no apparent growth defects, they were more resistant to gentamicin when compared to those with the wild-type menD gene. Our work suggests that menadione is involved in the production of the S. aureus capsule, and that amongst clinical isolates polymorphisms exist in the menD gene that confer the characteristic increased gentamicin resistance, but not the major growth defect associated with SCV phenotype.

Propensity for Early Metastatic Spread in Breast Cancer: Role of Tumor Vascularization Features and Tumor Immune Infiltrate

Simple SummaryNeoangiogenesis and different components of tumor microenvironment exert crucial roles in early metastatic spreading of breast cancer. Due to the paucity of available factors for breast cancer that can estimate the risk of metastasis or response to a given treatment, there is an important need for new, additional biomarkers of the tumor stroma that can be prognostic and predictive at the early stages of the disease. This review is focused on the current understanding of breast tumor environment characteristics (tumor vasculature and immune infiltrate) in order to incorporate them in diagnostic algorithms together with the assessment of hormone receptors (ER and PR) and of HER2 status.Breast cancer is a complex and highly heterogeneous disease consisting of various subtypes. It is classified into human epidermal growth receptor 2 (HER-2)-enriched, luminal A, luminal B and basal-like/triple negative (TNBC) breast cancer, based on histological and molecular features. At present, clinical decision-making in breast cancer is focused only on the assessment of tumor cells; nevertheless, it has been recognized that the tumor microenvironment (TME) plays a critical biologic role in breast cancer. This is constituted by a large group of immune and non-immune cells, but also by non-cellular components, such as several cytokines. TME is deeply involved in angiogenesis, immune-evasion strategies, and propensity for early metastatic spread, impacting on prognosis and prediction of response to specific treatments. In this review, we focused our attention on the early morphological changes of tumor microenvironment (tumor vasculature features, presence of immune and non-immune cells infiltrating the stroma, levels of cytokines) during breast cancer development. At the same time, we correlate these characteristics with early metastatic propensity (defined as synchronous metastasis or early recurrence) with particular attention to breast cancer subtypes.

Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells.

Cancer progresses by evading the immune system. Elucidating diverse immune evasion strategies is a critical step in the search for next-generation immunotherapies for cancer. Here we report that cancer cells can hijack the mitochondria from immune cells via physical nanotubes. Mitochondria are essential for metabolism and activation of immune cells. By using field-emission scanning electron microscopy, fluorophore-tagged mitochondrial transfer tracing and metabolic quantification, we demonstrate that the nanotube-mediated transfer of mitochondria from immune cells to cancer cells metabolically empowers the cancer cells and depletes the immune cells. Inhibiting the nanotube assembly machinery significantly reduced mitochondrial transfer and prevented the depletion of immune cells. Combining a farnesyltransferase and geranylgeranyltransferase 1 inhibitor, namely, L-778123, which partially inhibited nanotube formation and mitochondrial transfer, with a programmed cell death protein 1 immune checkpoint inhibitor improved the antitumour outcomes in an aggressive immunocompetent breast cancer model. Nanotube-mediated mitochondrial hijacking can emerge as a novel target for developing next-generation immunotherapy agents for cancer.

DNA double strand break position leads to distinct gene expression changes and regulates VSG switching pathway choice.

Antigenic variation is an immune evasion strategy used by Trypanosoma brucei that results in the periodic exchange of the surface protein coat. This process is facilitated by the movement of variant surface glycoprotein genes in or out of a specialized locus known as bloodstream form expression site by homologous recombination, facilitated by blocks of repetitive sequence known as the 70-bp repeats, that provide homology for gene conversion events. DNA double strand breaks are potent drivers of antigenic variation, however where these breaks must fall to elicit a switch is not well understood. To understand how the position of a break influences antigenic variation we established a series of cell lines to study the effect of an I-SceI meganuclease break in the active expression site. We found that a DNA break within repetitive regions is not productive for VSG switching, and show that the break position leads to a distinct gene expression profile and DNA repair response which dictates how antigenic variation proceeds in African trypanosomes.

Deletion of BCG_2432c from the Bacillus Calmette-Guérin vaccine enhances autophagy-mediated immunity against tuberculosis.

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is an attenuated live vaccine that provides insufficient protection against tuberculosis (TB), the underlying mechanisms for which remain unknown. Assuming that the BCG vaccine inherits immune evasive strategies from virulent parent M.bovis strains, we aimed to identify the associated genes and assess their effects on the vaccine efficacy. Three genes, BCG_3174, BCG_1782, and BCG_2432c, associated with immune evasion were first identified via bioinformatics analysis and then confirmed in the genome of M.bovis and 12 commercial BCG vaccine substrains using Polymerase Chain Reaction (PCR) and DNA sequencing. These genes were disrupted to develop mutant strains, and their effects on autophagy and their protective efficacy were further compared with the BCG vaccine in vitro and in vivo. Of the three identified genes, only the disruption of BCG_2432c, namely ΔBCG_2432c, conferred stronger protection against intranasal TB in vaccinated mice, when compared with the BCG vaccine. ΔBCG_2432c showed a stronger ability to trigger intracellular ROS-mediated complete autophagic flux in infected THP-1 cells that resulted in higher antigen presentation. The improved protection could be attributed to early and increased IFN-γ+ CD4+ TEM and IL-2+ CD4+ TCM cells in the spleens and lungs of ΔBCG_2432c-vaccinated mice. The insufficient efficacy of the BCG vaccine is attributable to the important autophagy-inhibition gene BCG_2432c that blocks the autophagosome-lysosome pathway of antigen presentation. ΔBCG_2432c provides a promising platform to either replace the current BCG vaccine or develop vaccines that are more effective against TB.

Recent Advances on the Innate Immune Response to Coxiella burnetii.

Coxiella burnetii is an obligate intracellular Gram-negative bacterium and the causative agent of a worldwide zoonosis known as Q fever. The pathogen invades monocytes and macrophages, replicating within acidic phagolysosomes and evading host defenses through different immune evasion strategies that are mainly associated with the structure of its lipopolysaccharide. The main transmission routes are aerosols and ingestion of fomites from infected animals. The innate immune system provides the first host defense against the microorganism, and it is crucial to direct the infection towards a self-limiting respiratory disease or the chronic form. This review reports the advances in understanding the mechanisms of innate immunity acting during C. burnetii infection and the strategies that pathogen put in place to infect the host cells and to modify the expression of specific host cell genes in order to subvert cellular processes. The mechanisms through which different cell types with different genetic backgrounds are differently susceptible to C. burnetii intracellular growth are discussed. The subsets of cytokines induced following C. burnetii infection as well as the pathogen influence on an inflammasome-mediated response are also described. Finally, we discuss the use of animal experimental systems for studying the innate immune response against C. burnetii and discovering novel methods for prevention and treatment of disease in humans and livestock.

Immune Escape Mechanisms in Intravascular Large B-Cell Lymphoma: A Molecular Cytogenetic and Immunohistochemical Study.

Intravascular large B-cell lymphomas (IVLBCLs) are rare extranodal LBCLs in which relapse is relatively frequent. We sought to further characterize potential immune escape mechanisms in IVLBCLs that newer therapies can exploit. A series of 33 IVLBCLs were evaluated for programmed cell death ligand 1 (PD-L1) and PD-L2 expression by immunohistochemistry (IHC), chromosomal alterations (CAs) in the PDL1/PDL2 locus by fluorescence in situ hybridization, and loss of major histocompatibility complex (MHC) class I and II expression by IHC. Cases were subclassified as classical (n = 22) or hemophagocytic syndrome (HPS)-associated (n = 11) variants. A total of 12 cases (39%; n = 12/31) expressed PD-L1 and/or PD-L2. CAs were seen in 7 cases (7/29 [24%]) and included gains, amplifications, and rearrangements. CAs in classical variant cases (24%; n = 5/21) included gains (n =1), gains with concurrent rearrangements (n = 2), and amplifications (n = 2). The 2 HPS-associated variant cases with CAs (25%; n = 2/8) both showed amplification, including 1 case with a concurrent rearrangement. A majority of cases with CAs (71%; n = 5/7) were PD-L1/PD-L2 IHC positive. Among PD-L1/PD-L2 IHC-positive cases, 45% harbored a CA. Loss of MHC class I and/or class II was seen in 27% (n = 9/33) of cases. Altogether, our data show that 65% (n = 20/31) of IVLBCLs may exploit immune evasion strategies through PD-L1/PD-L2 expression or downregulation of MHC proteins.

Biological Predictors of De Novo Tumors in Solid Organ Transplanted Patients During Oncological Surveillance: Potential Role of Circulating TERT mRNA.

Background De novo tumors are a major cause of morbidity and mortality after long-term solid organ transplantation. Chronic immunosuppression strongly affects solid organ transplanted (SOT) patients’ immune system by promoting immune evasion strategies and reactivations of viruses with oncogenic potential, ultimately leading to cancer onset. In this scenario, an oncological Surveillance Protocol integrated with biobanking of peripheral blood samples and evaluation of immunovirological and molecular parameters was activated for SOT patients at CRO-IRCCS Aviano, with the aim of identifying suitable biomarkers of cancer development.MethodsAn exploratory longitudinal study was designed based on two serial peripheral blood samples collected at least three months apart. Forty nine SOT patients were selected and stratified by tumor onset during follow-up. Spontaneous T-cell responses to EBV, CMV and tumor associated antigens, EBV-DNA and CMV-DNA loads, and circulating TERT mRNA levels were investigated.ResultsSignificantly higher levels of circulating TERT mRNA were observed 3.5-23.5 months before and close to the diagnosis of cancer as compared to tumor-free patients. Plasmatic TERT mRNA levels >97.73 copies/mL at baseline were significantly associated with the risk of developing de novo tumors (HR=4.0, 95%C.I. = 1.4-11.5, p=0.01). In particular, the risk significantly increased by 4% with every ten-unit increment in TERT mRNA (HR=1.04, 95%C.I. = 1.01-1.07, p=0.01).ConclusionsAlthough obtained in an exploratory study, our data support the importance of identifying early biomarkers of tumor onset in SOT patients useful to modulate the pace of surveillance visits.

Articles of Significant Interest In This Issue.

Nutrient acquisition systems and immune evasion strategies are key factors that contribute to host colonization and influence the overall pathogenic potential of a microorganism. The regulation of these factors is governed by metabolic cues, specifically the availability of glucose as a preferred carbon source. The research presented by Keffeler et al. (e00343-21) identifies CcpA as a major regulator of secondary nutrient acquisition and expands on the importance of GH18 family glycosyl hydrolases in Enterococcus faecalis. These glycosyl hydrolases contribute to the direct targeting of host glycoproteins both for nutrient acquisition as well as for potentially evading the host immune response.

T6SS translocates a micropeptide to suppress STING-mediated innate immunity by sequestering manganese

Cellular ionic concentrations are a central factor orchestrating host innate immunity, but no pathogenic mechanism that perturbs host innate immunity by directly targeting metal ions has yet been described. Here, we report a unique virulence strategy of Yersinia pseudotuberculosis (Yptb) involving modulation of the availability of Mn2+, an immunostimulatory metal ion in host cells. We showed that the Yptb type VI secretion system (T6SS) delivered a micropeptide, TssS, into host cells to enhance its virulence. The mutant strain lacking TssS (ΔtssS) showed substantially reduced virulence but induced a significantly stronger host innate immune response, indicating an antagonistic role of this effector in host antimicrobial immunity. Subsequent studies revealed that TssS is a Mn2+-chelating protein and that its Mn2+-chelating ability is essential for the disruption of host innate immunity. Moreover, we showed that Mn2+ enhances the host innate immune response to Yptb infection by activating the stimulator of interferon genes (STING)-mediated immune response. Furthermore, we demonstrated that TssS counteracted the cytoplasmic Mn2+ increase to inhibit the STING-mediated innate immune response by sequestering Mn2+ Finally, TssS-mediated STING inhibition sabotaged bacterial clearance in vivo. These results reveal a previously unrecognized bacterial immune evasion strategy involving modulation of the bioavailability of intracellular metal ions and provide a perspective on the role of the T6SS in pathogenesis.

217 Tofacitinib suppresses IL-10/IL-10R signaling and modulates host defense responses in human macrophages

JAK inhibitors are increasingly used in dermatology. Despite broad inhibitory effects on cytokine signaling cascades, they only modestly increase the risk for infectious diseases. To address molecular mechanisms underlying this unexpected clinical observation, we investigated how tofacintib, a first-in-class JAK inhibitor, regulates host defense responses in TLR4-activated human macrophages. Specifically, we asked if tofacitinib inhibits anti-inflammatory IL-10 signaling, thereby counteracting downregulation of inflammatory, host-protective pathways. We found that tofacitinib blocked macrophage responses to IL-10 at the level of STAT3 phosphorylation. Furthermore, TLR4-induced, auto-/paracrine IL-10/IL-10R activation promoted expression of hepcidin, the master regulator of iron metabolism, resulting in intracellular iron sequestration. In contrast, auto-/paracrine IL-10/IL-10R activation repressed expression of cathelicidin antimicrobial peptide, as well as antigen-presenting molecules, thus together, inducing a pathogen-favoring environment. While tofacitinib further repressed cathelicidin, it prevented induction of intracellular hepcidin, and restored expression of antigen-presentation molecules in TLR4-activated macrophages. Our study supports the concept that induction of IL-10/IL-10R signaling drives a complex immune evasion strategy of intracellular microbes. Moreover, we conclude that tofacitinib has diverging effects on macrophage host response pathways, and we identify the TLR4-IL-10-STAT3-hepcidin axis as a potential therapeutic target to counteract immune evasion.

Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis.

STING is a nodal point for cellular innate immune response to microbial infections, autoimmunity and cancer; it triggers the synthesis of the antiviral proteins, type I interferons. Many DNA viruses, including Herpes Simplex Virus 1 (HSV1), trigger STING signaling causing inhibition of virus replication. Here, we report that HSV1 evades this antiviral immune response by inducing a cellular microRNA, miR-24, which binds to the 3’ untranslated region of STING mRNA and inhibits its translation. Expression of the gene encoding miR-24 is induced by the transcription factor AP1 and activated by MAP kinases in HSV1-infected cells. Introduction of exogenous miR-24 or prior activation of MAPKs, causes further enhancement of HSV1 replication in STING-expressing cells. Conversely, transfection of antimiR-24 inhibits virus replication in those cells. HSV1 infection of mice causes neuropathy and death; using two routes of infection, we demonstrated that intracranial injection of antimiR-24 alleviates both morbidity and mortality of the infected mice. Our studies reveal a new immune evasion strategy adopted by HSV1 through the regulation of STING and demonstrates that it can be exploited to enhance STING’s antiviral action.

The MAVS Immune Recognition Pathway in Viral Infection and Sepsis.

Significance: It is estimated that close to 50 million cases of sepsis result in over 11 million annual fatalities worldwide. The pathognomonic feature of sepsis is a dysregulated inflammatory response arising from viral, bacterial, or fungal infections. Immune recognition of pathogen-associated molecular patterns is a hallmark of the host immune defense to combat microbes and to prevent the progression to sepsis. Mitochondrial antiviral signaling protein (MAVS) is a ubiquitous adaptor protein located at the outer mitochondrial membrane, which is activated by the cytosolic pattern recognition receptors, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation associated gene 5 (MDA5), following binding of viral RNA agonists. Recent Advances: Substantial progress has been made in deciphering the activation of the MAVS pathway with its interacting proteins, downstream signaling events (interferon [IFN] regulatory factors, nuclear factor kappa B), and context-dependent type I/III IFN response. Critical Issues: In the evolutionary race between pathogens and the host, viruses have developed immune evasion strategies for cleavage, degradation, or blockade of proteins in the MAVS pathway. For example, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M protein and ORF9b protein antagonize MAVS signaling and a protective type I IFN response. Future Directions: The role of MAVS as a sensor for nonviral pathogens, host cell injury, and metabolic perturbations awaits better characterization in the future. New technical advances in multidimensional single-cell analysis and single-molecule methods will accelerate the rate of new discoveries. The ultimate goal is to manipulate MAVS activities in the form of immune-modulatory therapies to combat infections and sepsis. Antioxid. Redox Signal. 35, 1376-1392.

SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response.

ABSTRACTNewly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5-mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARS-CoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients.

Tofacitinib Suppresses IL-10/IL-10R Signaling and Modulates Host Defense Responses in Human Macrophages

Jak inhibitors are increasingly used in dermatology. Despite broad inhibitory effects on cytokine signaling cascades, they only modestly increase the risk for infectious diseases. To address the molecular mechanisms underlying this unexpected clinical observation, we investigated how tofacintib (tofa), a first-in-class Jak inhibitor, regulates host defense responses in toll-like receptor 4-activated human macrophages. Specifically, we asked whether tofa inhibits anti-inflammatory IL-10 signaling, thereby counteracting the downregulation of inflammatory, host-protective pathways. We found that tofa blocked macrophage responses to IL-10 at the level of signal transducer and activator of transcription 3 phosphorylation. Furthermore, toll-like receptor 4-induced, autocrine/paracrine IL-10/IL-10R activation promoted the expression of hepcidin, the master regulator of iron metabolism, resulting in intracellular iron sequestration. In contrast, autocrine/paracrine IL-10/IL-10R activation repressed the expression of cathelicidin antimicrobial peptide as well as antigen-presenting molecules, thus together, inducing a pathogen-favoring environment. Although tofa further repressed cathelicidin, it prevented the induction of intracellular HAMP and restored the expression of antigen-presentation molecules in toll-like receptor 4-activated macrophages. Our study supports the concept that induction of IL-10/IL-10R signaling drives a complex immune evasion strategy of intracellular microbes. Moreover, we conclude that tofa has diverging effects on macrophage host response pathways, and we identify the toll-like receptor 4-IL-10-signal transducer and activator of transcription 3-HAMP axis as a potential therapeutic target to counteract immune evasion.

Crucial role of glucosylceramide synthase in the regulation of stem cell-like cancer cells in B16F10 murine melanoma.

Cancer stem cells render a complex cascade of events that facilitates highly invasive melanoma malignancy. Interplay between immunocytes and cancer stem cells within tumor microenvironment with the participation of sphingolipid signaling mediators skews the immune evasion strategies towardmetastatic neoplasm. In this context, we aimed to explore the functional aspect of glucosylceramide synthase (GCS), a key enzyme of sphingolipid biosynthesis in the maintenance of melanoma stem cell-like cancer cells (CSCs). Our findings demonstrated that tumor hypoxia was responsible for elevated GCS expression in melanoma, which was correlated with substantially increased melanoma CSCs. Moreover, hypoxia-induced TGF-β from TAMs and Tregs promoted GCS induction in B16F10 murine melanoma CSCs via PKCα signaling and facilitated the expansion of melanoma CSCs. Interestingly, GCS ablation hindered the immunosuppressiveness of TAMs and Tregs. Therefore, our study for the first time demonstrated a novel paracrine pathway of melanoma CSC maintenance and tumorigenicity, exploiting the bidirectional signaling with immunocytes. Furthermore, our study showed that the combinatorial immunotherapy involving immunomodulators like Mw and DTA-1 repressed CSC pool affecting GCS functions in advanced-stage B16F10 murine melanoma tumor. Moreover, GCS inhibition sensitized conventional chemotherapeutic drug-resistant melanoma CSCs to the genotoxic drugs paving the way towardselective melanoma treatment. Better therapeutic efficacy with inhibition of GCS and CSC depletion suggests a crucial role of GCS in melanoma treatment, therefore, implying its application concerning clinical challenges of chemotherapy resistance leading to prolonged survival.

Immune Landscape of CMV Infection in Cancer Patients: From "Canonical" Diseases Toward Virus-Elicited Oncomodulation.

Human Cytomegalovirus (HCMV) is an immensely pervasive herpesvirus, persistently infecting high percentages of the world population. Despite the apparent robust host immune responses, HCMV is capable of replicating, evading host defenses, and establishing latency throughout life by developing multiple immune-modulatory strategies. HCMV has coexisted with humans mounting various mechanisms to evade immune cells and effectively win the HCMV-immune system battle mainly through maintaining its viral genome, impairing HLA Class I and II molecule expression, evading from natural killer (NK) cell-mediated cytotoxicity, interfering with cellular signaling, inhibiting apoptosis, escaping complement attack, and stimulating immunosuppressive cytokines (immune tolerance). HCMV expresses several gene products that modulate the host immune response and promote modifications in non-coding RNA and regulatory proteins. These changes are linked to several complications, such as immunosenescence and malignant phenotypes leading to immunosuppressive tumor microenvironment (TME) and oncomodulation. Hence, tumor survival is promoted by affecting cellular proliferation and survival, invasion, immune evasion, immunosuppression, and giving rise to angiogenic factors. Viewing HCMV-induced evasion mechanisms will play a principal role in developing novel adapted therapeutic approaches against HCMV, especially since immunotherapy has revolutionized cancer therapeutic strategies. Since tumors acquire immune evasion strategies, anti-tumor immunity could be prominently triggered by multimodal strategies to induce, on one side, immunogenic tumor apoptosis and to actively oppose the immune suppressive microenvironment, on the other side.