Ligand-receptor Axis Research Articles

Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity.

The peritoneal cavity (PerC) is an important site for immune responses to infection and cancer metastasis. Yet few ligand-receptor axes are known to preferentially govern immune cell accumulation in this compartment. GPR34 is a lysophosphatidylserine (lysoPS)-responsive receptor that frequently harbors gain-of-function mutations in mucosa-associated B cell lymphoma. Here, we set out to test the impact of a GPR34 knock-in (KI) allele in the B-lineage. We report that GPR34 KI promotes the PerC accumulation of plasma cells (PC) and memory B cells (MemB). These KI cells migrate robustly to lysoPS ex vivo, and the KI allele synergizes with a Bcl2 transgene to promote MemB but not PC accumulation. Gene expression and labeling studies reveal that GPR34 KI enhances PerC MemB proliferation. Both KI PC and MemB are specifically enriched at the omentum, a visceral adipose tissue containing fibroblasts that express the lysoPS-generating PLA1A enzyme. Adoptive transfer and chimera experiments revealed that KI PC and MemB maintenance in the PerC is dependent on stromal PLA1A. These findings provide in vivo evidence that PLA1A produces lysoPS that can regulate GPR34-mediated immune cell accumulation at the omentum.

New potential ligand-receptor axis involved in tissue repair as therapeutic targets in progressive multiple sclerosis.

Progressive multiple sclerosis (PMS) represents the worsening phase of the disease by accumulative neurodegeneration and disability, mainly refractory to current treatments. The therapeutic options remain challenging based partially on the lack of understanding of the pathogenic mechanisms but also because the early dogma was centered on neuroinflammation, overshadowing the critical role of the tissue repair process. The tissue repair target should necessarily start early in disease development and PMS should combine anti-inflammatory and neuroprotective therapeutic strategies. Increasing preclinical evidence, together with the new era of omics applied on frozen human brain tissue, shed light on some ligand receptors axis, such as GAS6/TYRO3 and PROS1/AXL required to dampen inflammation, promote tissue repair and engage remyelination, at the early stages of multiple sclerosis (MS) as a critical step in preventing or stopping neurodegeneration. Here, we will discuss those receptor/ligand pairs that could be targetable for therapeutic intervention in progressive MS disease. Significance Statement The aim for PMS should be to combine anti-inflammatory and neuroprotective therapeutic strategies based on early intervention. The TYRO3, AXL, and MERTK (TAM) signaling axis, particularly GAS6/TYRO3 and PROS1/AXL, which are involved in tempering inflammation, promoting tissue repair, and engaging remyelination, could significantly benefit patients at the early PMS.

Unraveling Treg dysfunction and homing in atherosclerosis through the CCR5-CCL5/CCL4/CCL3 receptor-ligand axis

Unraveling Treg dysfunction and homing in atherosclerosis through the CCR5-CCL5/CCL4/CCL3 receptor-ligand axis

Phosphatidylserine-incorporated exosome mimetics encapsulating CXCR3 antagonist alleviate osteoporosis.

Exosomes derived from mesenchymal stem cells are an active area of research due to their therapeutic potential in treating osteoporosis. To further harness their therapeutic performance in modulating bone resorption, we have equipped exosomes with osteoclast-targeting moieties on their surface as well as chemokine receptor antagonists blocking osteoclast recruitment. Phosphatidylserine (PS), a membrane lipid exerting immunosuppressive and phagocytic signals, was incorporated in the membrane of exosome mimetics (EMs) to achieve a marked affinity for osteoclast precursors and potential anti-resorptive effects. We also aimed to tackle a CXCL9-CXCR3 ligand-receptor axis, a critical signaling axis in regulating osteoclast precursor recruitment and differentiation at bone resorption sites, by encapsulating a chemical antagonist of CXCR3, AMG487, in the PS-incorporated EMs (PS-EMs). The osteoclast-targeting PS-EMs loaded with AMG487 effectively protected against bone loss in an ovariectomized mouse model. Our findings demonstrate the great promise of PS-EMs as anti-resorptive nanotherapies for alleviating osteoporosis.

Abstract 1553: S1PR1 directs tumorsphere proliferation in ovarian cancer

Abstract Despite the clinical efforts to improve detection and treatment of high-grade serous ovarian cancer (HGSOC), half of diagnosed women will die every year because of this disease. Notably, nearly all of them present with ascites at diagnosis, which is directly associated with poor prognosis. Malignant ascites production occurs when ovarian cancer cells shed from the primary tumor, creating a selective pressure environment that threatens their survival. Therefore, cancer cells cluster into tumorspheres, the main metastatic units in HGSOC. In recent years, valuable insights into the mutational and immunological landscapes of HGSOC have been gained. However, there is scarce evidence on the precise molecular mechanisms that enable tumorspheres to surpass the ascites bottleneck and metastasize. In this work, our group addresses this knowledge gap by deciphering the role of S1PR1 in ovarian tumorsphere biology. In this study, ascites samples and Formalin-Fixed Paraffin-Embedded (FFPE) tumors and peritoneal metastases from a cohort of 32 treatment-naïve HGSOC patients have been used. Furthermore, 3D spheroid models from four different ovarian cancer cell lines have also been developed for in vitro and in vivo assays. Our results indicate that up to 60% of cells within HGSOC tumorspheres are proliferating due to an increased expression of pro-proliferative receptors. Thus, cancer cells within tumorspheres that overexpress these receptors might benefit from autocrine and paracrine signaling through release of their ligands. In this work, we have identified S1P-S1PR1 as one of these ligand-receptor axes, which promotes an autocrine positive loop that increases the intermediates of sphingolipid metabolism in ovarian cancer spheroids. Here, we demonstrate that S1PR1 is highly expressed in ascites tumorspheres and, in consequence, overexpressed in metastases in comparison with primary tumors. Furthermore, we also report that proliferation levels of ovarian cancer spheroids positively correlate with S1PR1 endogenous expression. Consistently, these levels are significantly reduced when S1PR1 is knocked out or pharmacologically inhibited. In addition, our results indicate that MEK1/2-ERK is the key downstream pro-mitogenic pathway of S1PR1 in HGSOC tumorspheres, and that its pharmacological inhibition is effective in reducing growth and number of disseminations in vivo. Conclusively, our group is the first one in reporting that the axis S1P-S1PR1-MEK1/2 is the main proliferative mechanism in HGSOC tumorspheres, providing them with a selective advantage and, consequently, a greater metastatic potential. The preclinical findings presented here may represent an opportunity to further explore targeted therapeutic strategies to hamper disease progression in ovarian cancer patients with the poorest outcome. Citation Format: Núria Gendrau-Sanclemente, Agnès Figueras, Kristina Gracova, Elisenda Alsina-Sanchís, Juan Antonio Marín-Jiménez, Josefina Casas, August Vidal, Xavier Matias-Guiu, Sergi Fernandez-Gonzalez, Marc Barahona, Lola Martí, Jordi Ponce, Francesc Viñals. S1PR1 directs tumorsphere proliferation in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1553.

Chemokine Ligand-Receptor Axes for Therapeutic Targeting During Skin Regeneration

Chemokine Ligand-Receptor Axes for Therapeutic Targeting During Skin Regeneration

Alpha-1 antitrypsin inhibits fractalkine-mediated monocyte-lung endothelial cell interactions.

Chronic obstructive pulmonary disease (COPD) is characterized by nonresolving inflammation fueled by breach in the endothelial barrier and leukocyte recruitment into the airspaces. Among the ligand-receptor axes that control leukocyte recruitment, the full-length fractalkine ligand (CX3CL1)-receptor (CX3CR1) ensures homeostatic endothelial-leukocyte interactions. Cigarette smoke (CS) exposure and respiratory pathogens increase expression of endothelial sheddases, such as a-disintegrin-and-metalloproteinase-domain 17 (ADAM17, TACE), inhibited by the anti-protease α-1 antitrypsin (AAT). In the systemic endothelium, TACE cleaves CX3CL1 to release soluble CX3CL1 (sCX3CL1). During CS exposure, it is not known whether AAT inhibits sCX3CL1 shedding and CX3CR1+ leukocyte transendothelial migration across lung microvasculature. We investigated the mechanism of sCX3CL1 shedding, its role in endothelial-monocyte interactions, and AAT effect on these interactions during acute inflammation. We used two, CS and lipopolysaccharide (LPS) models of acute inflammation in transgenic Cx3cr1gfp/gfp mice and primary human endothelial cells and monocytes to study sCX3CL1-mediated CX3CR1+ monocyte adhesion and migration. We measured sCX3CL1 levels in plasma and bronchoalveolar lavage (BALF) of individuals with COPD. Both sCX3CL1 shedding and CX3CR1+ monocytes transendothelial migration were triggered by LPS and CS exposure in mice, and were significantly attenuated by AAT. The inhibition of monocyte-endothelial adhesion and migration by AAT was TACE-dependent. Compared with healthy controls, sCX3CL1 levels were increased in plasma and BALF of individuals with COPD, and were associated with clinical parameters of emphysema. Our results indicate that inhibition of sCX3CL1 as well as AAT augmentation may be effective approaches to decrease excessive monocyte lung recruitment during acute and chronic inflammatory states.NEW & NOTEWORTHY Our novel findings that AAT and other inhibitors of TACE, the sheddase that controls full-length fractalkine (CX3CL1) endothelial expression, may provide fine-tuning of the CX3CL1-CX3CR1 axis specifically involved in endothelial-monocyte cross talk and leukocyte recruitment to the alveolar space, suggests that AAT and inhibitors of sCX3CL1 signaling may be harnessed to reduce lung inflammation.

T-cell immunoglobulin and mucin-domain containing-3 (TIM-3): Solving a key puzzle in autoimmune diseases.

Dysfunctional immune cells participate in the pathogenesis of a variety of autoimmune diseases, although the specific mechanisms remain elusive and effective clinical interventions are lacking. Recent research on immune checkpoint molecules has revealed significant expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) on the surfaces of various immune cells. These include different subsets of T cells, macrophages, dendritic cells, natural killer cells, and mast cells. Further investigation into its protein structure, ligands, and intracellular signaling pathway activation mechanisms has found that TIM-3, by binding with different ligands, is involved in the regulation of crucial biological processes such as proliferation, apoptosis, phenotypic transformation, effector protein synthesis, and cellular interactions of various immune cells. The TIM-3-ligand axis plays a pivotal role in the pathogenesis of numerous conditions, including autoimmune diseases, infections, cancers, transplant rejection, and chronic inflammation. This article primarily focuses on the research findings of TIM-3 in the field of autoimmune diseases, with a special emphasis on the structure and signaling pathways of TIM-3, its types of ligands, and the potential mechanisms implicated in systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, as well as other autoimmune diseases and chronic inflammation. The latest research results in the field of immunology suggest that TIM-3 dysfunction affects various immune cells and participates in the pathogenesis of diseases. Monitoring the activity of its receptor-ligand axis can serve as a novel biological marker for disease clinical diagnosis and prognosis evaluation. More importantly, the TIM-3-ligand axis and the downstream signaling pathway molecules may become key targets for targeted intervention treatment of autoimmune-related diseases.

Biomembrane force probe (BFP): Design, advancements, and recent applications to live-cell mechanobiology.

Mechanical forces play a vital role in biological processes at molecular and cellular levels, significantly impacting various diseases such as cancer, cardiovascular disease, and COVID-19. Recent advancements in dynamic force spectroscopy (DFS) techniques have enabled the application and measurement of forces and displacements with high resolutions, providing crucial insights into the mechanical pathways underlying these diseases. Among DFS techniques, the biomembrane force probe (BFP) stands out for its ability to measure bond kinetics and cellular mechanosensing with pico-newton and nano-meter resolutions. Here, a comprehensive overview of the classical BFP-DFS setup is presented and key advancements are emphasized, including the development of dual biomembrane force probe (dBFP) and fluorescence biomembrane force probe (fBFP). BFP-DFS allows us to investigate dynamic bond behaviors on living cells and significantly enhances the understanding of specific ligand-receptor axes mediated cell mechanosensing. The contributions of BFP-DFS to the fields of cancer biology, thrombosis, and inflammation are delved into, exploring its potential to elucidate novel therapeutic discoveries. Furthermore, future BFP upgrades aimed at improving output and feasibility are anticipated, emphasizing its growing importance in the field of cell mechanobiology. Although BFP-DFS remains a niche research modality, its impact on the expanding field of cell mechanobiology is immense.

Elevated sHLA-G plasma levels post chemotherapy combined with ILT-2 rs10416697C allele status of the sHLA-G-related receptor predict poorest disease outcome in early triple-negative breast cancer patients.

Triple negative breast cancer (TNBC) shows an aggressive growing and spreading behavior and has limited treatment options, often leading to inferior disease outcome. Therefore, surrogate markers are urgently needed to identify patients at high risk of recurrence and more importantly, to identify additional therapeutic targets enabling further treatment options. Based on the key role of the non-classical human leukocyte antigen G (HLA-G) and its related receptor immunoglobulin-like transcript receptor-2 (ILT-2) in immune evasion mechanisms of tumors, members of this ligand-receptor axis appear to be promising tool for both, defining risk groups and potential therapeutic targets. To follow this, sHLA-G levels before and after chemotherapy (CT), HLA-G 3' UTR haplotypes, and allele variations rs10416697 at the distal gene promoter region of ILT-2 were defined in healthy female controls and early TNBC patients. The results obtained were associated with clinical status, presence of circulating tumor cell (CTC) subtypes, and disease outcome of patients in terms of progression-free or overall survival. sHLA-G plasma levels were increased in TNBC patients post-CT compared to levels of patients pre-CT or controls. High post-CT sHLA-G levels were associated with the development of distant metastases, the presence of ERCC1 or PIK3CA-CTC subtypes post-CT, and poorer disease outcome in uni- or multivariate analysis. HLA-G 3' UTR genotypes did not influence disease outcome but ILT-2 rs10416697C allele was associated with AURKA-positive CTC and with adverse disease outcome by uni- and multivariate analysis. The prognostic value of the combined risk factors (high sHLA-G levels post-CT and ILT-2 rs10416697C allele carrier status) was an even better independent indicator for disease outcome in TNBC than the lymph nodal status pre-CT. This combination allowed the identification of patients with high risk of early progression/death with positive nodal status pre-CT or with non-pathological complete therapy response. The results of this study highlight for the first time that the combination of high levels of sHLA-G post-CT with ILT-2 rs10416697C allele receptor status is a promising tool for the risk assessment of TNBC patients and support the concept to use HLA-G/ILT-2 ligand-receptor axis as therapeutic targets.

Highlights from Recent Cancer Literature.

Highlights from Recent Cancer Literature.

CEP192 is a novel prognostic marker and correlates with the immune microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) responds poorly to standard chemotherapy or targeted therapy; hence, exploration for novel therapeutic targets is urgently needed. CEP192 protein is indispensable for centrosome amplification, which has been extensively characterized in both hematological malignancies and solid tumors. Here, we combined bioinformatics and experimental approaches to assess the potential of CEP192 as a prognostic and therapeutic target in HCC. CEP192 expression increased with tumor stage and was associated with poor clinicopathologic features, frequent recurrence, and higher mortality. Upon single-cell RNA sequencing, CEP192 was found to be involved in the proliferation and self-renewal of hepatic progenitor-like cells. This observation was further evidenced using CEP192 silencing, which prevented tumor cell proliferation and self-renewal by arresting cells in the G0/G1 phase of the cell cycle. Notably, CEP192 was highly correlated with multiple tumor-associated cytokine ligand–receptor axes, including IL11–IL11RA, IL6–IL6R, and IL13–IL13RA1, which could promote interactions between hepatic progenitor-like cells, PLVAP+ endothelial cells, tumor-associated macrophages, and CD4+ T cells. Consequently, CEP192 expression was closely associated with an immunosuppressive tumor microenvironment and low immunophenoscores, making it a potential predictor of response to immune checkpoint inhibitors. Taken together, our results unravel a novel onco-immunological role of CEP192 in establishing the immunosuppressive tumor microenvironment and provide a novel biomarker, as well as a potential target for therapeutic intervention of HCC.

Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats.

The maternal immune activation produced by the systemic administration of lipopolysaccharide (LPS) in rats provides valuable insights into the basis of behavioural schizophrenia-like disturbances and biochemical changes in the brains of the offspring, such as microglial activation. Regarding therapy, antipsychotics continually constitute the cornerstone of schizophrenia treatment. To their various efficacy and side effects, as well as not fully recognised mechanisms of action, further characteristics have been suggested, including an anti-inflammatory action via the impact on neuron–microglia axes responsible for inhibition of microglial activation. Therefore, in the present study, we sought to determine whether chronic treatment with chlorpromazine, quetiapine or aripiprazole could influence schizophrenia-like behavioural disturbances at the level of sensorimotor gating in male offspring prenatally exposed to LPS. Simultaneously, we wanted to explore if the chosen antipsychotics display a positive impact on the neuroimmunological parameters in the brains of these adult animals with a special focus on the ligand-receptor axes controlling neuron–microglia communication as well as pro- and anti-inflammatory factors related to the microglial activity. The results of our research revealed the beneficial effect of quetiapine on deficits in sensorimotor gating observed in prenatally LPS-exposed offspring. In terms of axes controlling neuron–microglia communication and markers of microglial reactivity, we observed a subtle impact of quetiapine on hippocampal Cx3cl1 and Cx3cr1 levels, as well as cortical Cd68 expression. Hence, further research is required to fully define and explain the involvement of quetiapine and other antipsychotics in Cx3cl1-Cx3cr1 and/or Cd200-Cd200r axes modulation and inflammatory processes in the LPS-based model of schizophrenia-like disturbances.

Organizing structural principles of the IL-17 ligand–receptor axis

The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases1. The compositions and structures of functional IL-17 family ligand–receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses2. Here we studied IL-25–IL-17RB binary and IL-25–IL-17RB–IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25–IL-17RB–IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25–IL-17RB homodimer is flanked by two ‘wing-like’ IL-17RA co-receptors through a ‘tip-to-tip’ geometry that is the key receptor–receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB–IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A–IL-17RA and IL-17A–IL-17RA–IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor.

RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development

RTN4-binding proteins were widely studied as "NoGo" receptors, but their physiological interactors and roles remain elusive. Similarly, BAI adhesion-GPCRs were associated with numerous activities, but their ligands and functions remain unclear. Using unbiased approaches, we observed an unexpected convergence: RTN4 receptors are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. In the 1.65Å crystal structure of the BAI1/RTN4-receptor complex, C-mannosylation of tryptophan and O-fucosylation of threonine in the BAI TSR-domains creates a RTN4-receptor/BAI interface shaped by unusual glycoconjugates that enables high-affinity interactions. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation by differential binding to glial versus neuronal BAIs, thereby controlling neural network activity. Thus, BAI binding to RTN4/NoGo receptors represents a receptor-ligand axis that, enabled by rare post-translational modifications, controls development of synaptic circuits.

Microglia Mediate the Occurrence and Development of Alzheimer's Disease Through Ligand-Receptor Axis Communication.

Alzheimer’s disease (AD) is a common neurodegenerative disease. Its onset is insidious and its progression is slow, making diagnosis difficult. In addition, its underlying molecular and cellular mechanisms remain unclear. In this study, clustering analysis was performed on single-cell RNA sequencing (scRNA-seq) data from the prefrontal cortex of 48 AD patients. Each sample module was identified to be a specific AD cell type, eight main brain cell types were identified, and the dysfunctional evolution of each cell type was further explored by pseudo-time analysis. Correlation analysis was then used to explore the relationship between AD cell types and pathological characteristics. In particular, intercellular communication between neurons and glial cells in AD patients was investigated by cell communication analysis. In patients, neuronal cells and glial cells significantly correlated with pathological features, and glial cells appear to play a key role in the development of AD through ligand-receptor axis communication. Marker genes involved in communication between these two cell types were identified using five types of modeling: logistic regression, multivariate logistic regression, least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM). LASSO modeling identified CXCR4, EGFR, MAP4K4, and IGF1R as key genes in this communication. Our results support the idea that microglia play a role in the occurrence and development of AD through ligand-receptor axis communication. In particular, our analyses identify CXCR4, EGFR, MAP4K4, and IGF1R as potential biomarkers and therapeutic targets in AD.

Manipulating the NKG2D Receptor-Ligand Axis Using CRISPR: Novel Technologies for Improved Host Immunity.

The activating immune receptor natural killer group member D (NKG2D) and its cognate ligands represent a fundamental surveillance system of cellular distress, damage or transformation. Signaling through the NKG2D receptor-ligand axis is critical for early detection of viral infection or oncogenic transformation and the presence of functional NKG2D ligands (NKG2D-L) is associated with tumor rejection and viral clearance. Many viruses and tumors have developed mechanisms to evade NKG2D recognition via transcriptional, post-transcriptional or post-translational interference with NKG2D-L, supporting the concept that circumventing immune evasion of the NKG2D receptor-ligand axis may be an attractive therapeutic avenue for antiviral therapy or cancer immunotherapy. To date, the complexity of the NKG2D receptor-ligand axis and the lack of specificity of current NKG2D-targeting therapies has not allowed for the precise manipulation required to optimally harness NKG2D-mediated immunity. However, with the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins, novel opportunities have arisen in the realm of locus-specific gene editing and regulation. Here, we give a brief overview of the NKG2D receptor-ligand axis in humans and discuss the levels at which NKG2D-L are regulated and dysregulated during viral infection and oncogenesis. Moreover, we explore the potential for CRISPR-based technologies to provide novel therapeutic avenues to improve and maximize NKG2D-mediated immunity.

Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer.

Drug-induced resistance, or tolerance, is an emerging yet poorly understood failure of anticancer therapy. The interplay between drug-tolerant cancer cells and innate immunity within the tumor, the consequence on tumor growth, and therapeutic strategies to address these challenges remain undescribed. Here, we elucidate the role of taxane-induced resistance on natural killer (NK) cell tumor immunity in triple-negative breast cancer (TNBC) and the design of spatiotemporally controlled nanomedicines, which boost therapeutic efficacy and invigorate "disabled" NK cells. Drug tolerance limited NK cell immune surveillance via drug-induced depletion of the NK-activating ligand receptor axis, NK group 2 member D, and MHC class I polypeptide-related sequence A, B. Systems biology supported by empirical evidence revealed the heat shock protein 90 (Hsp90) simultaneously controls immune surveillance and persistence of drug-treated tumor cells. On the basis of this evidence, we engineered a "chimeric" nanotherapeutic tool comprising taxanes and a cholesterol-tethered Hsp90 inhibitor, radicicol, which targets the tumor, reduces tolerance, and optimally reprimes NK cells via prolonged induction of NK-activating ligand receptors via temporal control of drug release in vitro and in vivo. A human ex vivo TNBC model confirmed the importance of NK cells in drug-induced death under pressure of clinically approved agents. These findings highlight a convergence between drug-induced resistance, the tumor immune contexture, and engineered approaches that consider the tumor and microenvironment to improve the success of combinatorial therapy. SIGNIFICANCE: This study uncovers a molecular mechanism linking drug-induced resistance and tumor immunity and provides novel engineered solutions that target these mechanisms in the tumor and improve immunity, thus mitigating off-target effects.

Genetic Variants of the NKG2C/HLA-E Receptor-Ligand Axis Are Determinants of Progression-Free Survival and Therapy Outcome in Aggressive B-Cell Lymphoma.

Simple SummaryNKG2C and its ligand HLA-E represent key molecules for NK cell-mediated immune responsiveness. However, the impact of genetic variants in NKG2C and HLA-E on clinical outcomes of aggressive B-cell non-Hodgkin lymphoma patients (B-NHL) has not been clarified. In this study, we analyzed the distribution of NKG2C deletion status and HLA-E variants in 441 patients and 192 healthy individuals. Homozygous deletion of NKG2C (NKG2C−/−) was more often found in high-risk patients compared to patients with a lower risk and consequently was associated with reduced 2-year progression-free survival. The HLA-E*01:01 allele frequency was increased in B-NHL patients and was strongly related with complete remission. Our results show that absence of NKG2C and HLA-E allelic variations is predictive for B-NHL outcome; while carriers of HLA-E*01:01 are characterized by high, complete remission rates, NKG2C−/− was rare, but associated with poorer outcome. Prospective validation of our results identifies patients that may benefit from risk-adapted therapy.Aggressive B-cell lymphomas account for the majority of non-Hodgkin lymphomas (B-NHL). NK cells govern the responses to anti-CD20 monoclonal antibodies and have emerged as attractive targets for immunotherapy in subtypes of B-NHL. NKG2C and its cognate ligand HLA-E represent key molecules for fine-tuning of NK cell-mediated immune responses. Here, we investigated the impact of genetic variants of NKG2C and HLA-E on clinical outcomes of 441 B-NHL patients. Homozygous deletion of NKG2C (NKG2C−/−) was three-fold increased in patients compared to 192 healthy controls. Among studied patients, NKG2C−/− was more abundant in International Prognostic Index (IPI) high-risk patients compared to patients with a lower IPI (p = 0.013). Strikingly, NKG2C−/− was associated with a significantly reduced 2-year PFS (progression-free survival) (p = 0.0062) and represented an independent risk factor for 2-year PFS in multivariate analysis (p = 0.005). For HLA-E, the cognate ligand of NKG2C, the HLA-E*01:01 allele frequency was increased in B-NHL patients compared to controls (p = 0.033) and was associated with complete remission in univariate (p = 0.034) and multivariate (p = 0.018) analysis. Our data suggest that NKG2C and HLA-E genotyping is a promising tool for both defining risk groups of aggressive B-NHL and predicting response to immune therapeutic approaches.

Chemokines as Drivers of the Autoimmune Destruction in Type 1 Diabetes: Opportunity for Therapeutic Intervention in Consideration of an Optimal Treatment Schedule.

Type 1 diabetes (T1D) is mainly precipitated by the destruction of insulin-producing β-cells in the pancreatic islets of Langerhans by autoaggressive T cells. The etiology of the disease is still not clear, but besides genetic predisposition the exposure to environmental triggers seems to play a major role. Virus infection of islets has been demonstrated in biopsies of T1D patients, but there is still no firm proof that such an infection indeed results in islet-specific autoimmunity. However, virus infection results in a local inflammation with expression of inflammatory factors, such as cytokines and chemokines that attract and activate immune cells, including potential autoreactive T cells. Many chemokines have been found to be elevated in the serum and expressed by islet cells of T1D patients. In mouse models, it has been demonstrated that β-cells express chemokines involved in the initial recruitment of immune cells to the islets. The bulk load of chemokines is however released by the infiltrating immune cells that also express multiple chemokine receptors. The result is a mutual attraction of antigen-presenting cells and effector immune cells in the local islet microenvironment. Although there is a considerable redundancy within the chemokine ligand-receptor network, a few chemokines, such as CXCL10, seem to play a key role in the T1D pathogenesis. Studies with neutralizing antibodies and investigations in chemokine-deficient mice demonstrated that interfering with certain chemokine ligand-receptor axes might also ameliorate human T1D. However, one important aspect of such a treatment is the time of administration. Blockade of the recruitment of immune cells to the site of autoimmune destruction might not be effective when the disease process is already ongoing. By that time, autoaggressive cells have already arrived in the islet microenvironment and a blockade of migration might even hold them in place leading to accelerated destruction. Thus, an anti-chemokine therapy makes most sense in situations where the cells have not yet migrated to the islets. Such situations include treatment of patients at risk already carrying islet-antigen autoantibodies but are not yet diabetic, islet transplantation recipients, and patients that have undergone a T cell reset as occurring after anti-CD3 antibody treatment.