Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice.

Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent virus neutralization and maximize oncolysis. Thus, we generated a chimeric virus, Delta-24-RGD-H43m, by replacing the capsid protein HVRs from the serotype 5-based Delta-24-RGD with those from the rare serotype 43. Delta-24-RGD-H43m evaded neutralizing anti-Ad5 antibodies and conferred a higher rate of long-term survival than Delta-24-RGD in glioma-bearing mice. Importantly, Delta-24-RGD-H43m activity was significantly more resistant to neutralizing antibodies present in sera of glioma patients treated with Delta-24-RGD during a phase 1 clinical trial. These findings provide a framework for a novel treatment of glioma patients that have developed immunity against Delta-24-RGD.

Identification of adipocyte plasma membrane-associated protein as a novel modulator of human cytomegalovirus infection.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that can cause disability in newborns and serious clinical diseases in immunocompromised patients. HCMV has a large genome with enormous coding potential; its viral particles are equipped with complicated glycoprotein complexes and can infect a wide range of human cells. Although multiple host cellular receptors interacting with viral glycoproteins have been reported, the mechanism of HCMV infection remains a mystery. Here we report identification of adipocyte plasma membrane-associated protein (APMAP) as a novel modulator active in the early stage of HCMV infection. APMAP is necessary for HCMV infection in both epithelial cells and fibroblasts; knockdown of APMAP expression significantly reduced HCMV infection of these cells. Interestingly, ectopic expression of human APMAP in cells refractory to HCMV infection, such as canine MDCK and murine NIH/3T3 cells, promoted HCMV infection. Furthermore, reduction in viral immediate early (IE) gene transcription at 6 h post infection and delayed nucleus translocation of tegument delivered pp65 at 4 h post infection were detected in APMAP-deficient cells but not in the wildtype cells. These results suggest that APMAP plays a role in the early stage of HCMV infection. Results from biochemical studies of APMAP and HCMV proteins suggest that APMAP could participate in HCMV infection through interaction with gH/gL containing glycoprotein complexes at low pH and mediate nucleus translocation of tegument pp65. Taken together, our results suggest that APMAP functions as a modulator promoting HCMV infection in multiple cell types and is an important player in the complex HCMV infection mechanism.

Determination of stress components in a complex stress condition using micro-Raman spectroscopy.

In this study, an iterative method using polarized Raman spectroscopy to quantitatively determine all the in-plane components of the stress tensor in semiconductor structures is presented. Raman experiments were conducted on silicon at different stress states. The results obtained by the proposed method were in good agreement with the given stress state. In addition, the effect of random errors of Raman shifts on the stress component calculation is discussed. In contrast to the conventional analytical solution, our iterative method can significantly reduce the random errors.

Dynamic prediction of optical and chromatic performances for a light-emitting diode array based on a thermal-electrical-spectral model.

Light-emitting diode (LED) arrays have attracted increased attention in the area of high power intelligent automotive headlamps because of their superiority in disposing of the power limit of an individual LED package and controllably luminous intensity and illumination pattern. The optical and chromatic performances of an LED array do not equal to the sum of individual LED packages' performances, as the thermal interactions between individual LED packages can't be ignored in the actual application. This paper presents a thermal-electrical-spectral (TES) model to dynamically predict the optical and chromatic performances of the LED array. The thermal-electrical (TE) model considering the thermal coupling effect in the LED array is firstly proposed to predict the case temperature of each individual LED package, and the Spectral power distributions (SPDs) of individual LED package is then decomposed by the extended Asym2sig model to extract the spectral characteristic parameters. Finally, the experimental measurements of the designed LED arrays operated under usage conditions are used to verify the TES model. Some validation case studies show that the prediction accuracy of the proposed TES model, which is expressed as a quadratic polynomial function of current and case temperature, can be achieved higher than 95%. Therefore, it can be concluded that this TES model offers a convenient method with high accuracy to dynamically predict the optical and chromatic performances of LED arrays at real usages.

High-performance humidity sensor using Schottky-contacted SnS nanoflakes for noncontact healthcare monitoring.

Humidity sensors based on flexible sensitive nanomaterials are very attractive in noncontact healthcare monitoring. However, the existing humidity sensors have some shortcomings such as limited sensitivity, narrow relative humidity (RH) range, and a complex process. Herein, we show that a tin sulphide (SnS) nanoflakes-based sensor presents high humidity sensing behaviour both in rigid and flexible substrate. The sensing mechanism based on the Schottky nature of a SnS-metal contact endows the as-fabricated sensor with a high response of 2491000% towards a wide RH range from 3% RH to 99% RH. The response and recovery time of the sensor are 6 s and 4 s, respectively. Besides, the flexible SnS nanoflakes-based humidity sensor with a polyimide substrate can be well attached to the skin and exhibits stable humidity sensing performance in the natural flat state and under bending loading. Moreover, the first-principles analysis is performed to prove the high specificity of SnS to the moisture (H2O) in the air. Benefiting from its promising advantages, we explore some application of the SnS nanoflakes-based sensors in detection of breathing patterns and non-contact finger tips sensing behaviour. The sensor can monitor the respiration pattern of a human being accurately, and recognize the movement of the fingertip speedily. This novel humidity sensor shows great promising application in physiological and physical monitoring, portable diagnosis system, and noncontact interface localization.

Correction: Liquid-phase exfoliated SnS as a semiconductor coating filler to enhance corrosion protection performance.

Correction for 'Liquid-phase exfoliated SnS as a semiconductor coating filler to enhance corrosion protection performance' by Hongyu Tang et al., Phys. Chem. Chem. Phys., 2019, 21, 18179-18187, DOI: 10.1039/C9CP03381E.

Polarized Raman spectroscopy-stress relationship considering shear stress effect.

This Letter uses polarized Raman spectroscopy as a "strain rosette" to quantitatively determine all the in-plane components of the stress tensor for (110) silicon. Through polarized Raman spectroscopy, Raman wavenumber shifts can be obtained at the same point with different polarization directions of the incident and/or scattered light. With at least three measured Raman shifts in different polarized directions, the three stress components of a surface that contains two non-equal normal stresses and one shear stress can be calculated accordingly. We develop an analytical and linear Raman wavenumber shift-stress relationship when shear stress is considered. The experimental results verify the theoretical predictions. It shows that the simple stress condition assumption may lead to erroneous results.

Liquid-phase exfoliated SnS as a semiconductor coating filler to enhance corrosion protection performance.

This paper presents the anti-corrosion application of polyvinylbutyral/tin sulfide (PVB/SnS) composites for the first time, where the liquid-phase exfoliated (LPE) SnS nanosheets are uniformly embedded in the PVB matrix. The measurement results of the potentiodynamic polarization, the electrochemical impedance spectroscopy (EIS) and the scanning electronic microscopy (SEM) show that PVB/SnS composite coatings show the excellent corrosion protection behavior for copper under 3.0% NaCl solution. Besides, we investigated the anti-corrosion performance with different contents of SnS nanosheets. The results show that embedding 0.1 wt% SnS nanosheets in the PVB matrix can greatly improve the anti-corrosion properties of the coating due to the enhanced "Labyrinth effect" of the coatings. In addition, the results of the molecular dynamic analysis further show the high interaction energy between PVB/SnS composites and copper, which is attributed to the high aspect-ratio of LPE-SnS nanosheets. Moreover, the scratch tests reveal that the PVB/SnS composite coatings exhibit weak corrosion-promotion activity, indicating a promising potential application in the corrosion protection of the metal surface for ocean engineering. The methods for enhancing the inhibited corrosion-promotion activity of the semiconductor material SnS-based composite coatings could be expanded to other n-type and p-type semiconductors.

Tunable electronic and optical properties of the WS2/IGZO heterostructure via an external electric field and strain: a theoretical study.

In this study, the structural, electronic and optical properties of a tungsten disulfide (WS2) hybrid with indium-gallium-zinc-oxide (IGZO) heterostructures were investigated based on density functional theory (DFT) calculations. According to the results of binding energy, charge density difference and electron localization function of heterostructures, we found that the WS2 and IGZO monolayers were bound to each other via non-covalent interactions with large binding energy. The calculated results illustrate that the AAii stacking pattern has an indirect band gap of 1.643 eV, while AAi and AB stacking patterns have maximum direct-gaps of 1.102 eV and 1.234 eV, respectively. Under an external E-field and mechanical strain, the response of the energy gap of the WS2/IGZO heterostructure monotonically decreased over a wide range, even with a semiconductor-metal transition. In addition, we investigated the optical properties of the heterostructure and found that it exhibits a much broad spectral responsivity (from visible light to deep UV light) and a more pronounced optical absorption than WS2 and IGZO monolayers. Moreover, the tensile strain could weaken the photoresponse of the heterostructure to the UV light and enhance the response for the visible light; under compressive strain, the heterostructure showed a strong absorption peak in the UV light. Meanwhile, a red-shift was observed under an external strain. All these unique and tunable properties indicate that the WS2/IGZO heterostructure is a good candidate for nanoelectronic and photoelectronic devices, such as field-effect transistors, flexible sensors, photodetectors and photonic devices.

Proteolytic single hinge cleavage of pertuzumab impairs its Fc effector function and antitumor activity in vitro and in vivo.

BACKGROUND: Proteolytic impairment of the Fc effector functions of therapeutic monoclonal antibodies (mAbs) can compromise their antitumor efficacy in the tumor microenvironment and may represent an unappreciated mechanism of host immune evasion. Pertuzumab is a human epidermal growth factor receptor 2 (HER2)-targeting antibody and has been widely used in the clinic in combination with trastuzumab for treatment of HER2-overexpressing breast cancer. Pertuzumab susceptibility to proteolytic hinge cleavage and its impact on the drug's efficacy has not been previously studied. METHODS: Pertuzumab was incubated with high and low HER2-expressing cancer cells and proteolytic cleavage in the lower hinge region was detected by western blotting. The single hinge cleaved pertuzumab (scIgG-P) was purified and evaluated for its ability to mediate antibody-dependent cellular cytotoxicity (ADCC) in vitro and anti-tumor efficacy in vivo. To assess the cleavage of trastuzumab (IgG-T) and pertuzumab (IgG-P) when simultaneously bound to the same cancer cell surface, F(ab')2 fragments of IgG-T or IgG-P were combined with the intact IgG-P and IgG-T, respectively, to detect scIgG generation by western blotting. RESULTS: Pertuzumab hinge cleavage occurred when the mAb was incubated with high HER2-expressing cancer cells. The hinge cleavage of pertuzumab caused a substantial loss of ADCC in vitro and reduced antitumor efficacy in vivo. The reduced ADCC function of scIgG-P was restored by an anti-hinge mAb specific for a cleavage site neoepitope. In addition, we constructed a protease-resistant version of the anti-hinge mAb that restored ADCC and the cell-killing functions of pertuzumab when cancer cells exressed a potent IgG hinge-cleaving protease. We also observed increased hinge cleavage of pertuzumab when combined with trastuzumab. CONCLUSION: The reduced Fc effector function of single hinge-cleaved pertuzumab can be restored by an anti-hinge mAb. The restoration effect indicated that immune function could be readily augmented when the damaged primary antibodies were bound to cancer cell surfaces. The anti-hinge mAb also restored Fc effector function to the mixture of proteolytically disabled trastuzumab and pertuzumab, suggesting a general therapeutic strategy to restore the immune effector function to protease-inactivated anticancer antibodies in the tumor microenvironment. The findings point to a novel tactic for developing breast cancer immunotherapy.

Targeting Human-Cytomegalovirus-Infected Cells by Redirecting T Cells Using an Anti-CD3/Anti-Glycoprotein B Bispecific Antibody.

The host immune response to human cytomegalovirus (HCMV) is effective against HCMV reactivation from latency, though not sufficient to clear the virus. T cells are primarily responsible for the control of viral reactivation. When the host immune system is compromised, as in transplant recipients with immunosuppression, HCMV reactivation and progressive infection can cause serious morbidity and mortality. Adoptive T cell therapy is effective for the control of HCMV infection in transplant recipients. However, it is a highly personalized therapeutic regimen and is difficult to implement in routine clinical practice. In this study, we explored a bispecific-antibody strategy to direct non-HCMV-specific T cells to recognize and exert effector functions against HCMV-infected cells. Using a knobs-into-holes strategy, we constructed a bispecific antibody in which one arm is specific for CD3 and can trigger T cell activation, while the other arm, specific for HCMV glycoprotein B (gB), recognizes and marks HCMV-infected cells based on the expression of viral gB on their surfaces. We showed that this bispecific antibody was able to redirect T cells with specificity for HCMV-infected cells in vitro In the presence of HCMV infection, the engineered antibody was able to activate T cells with no HCMV specificity for cytokine production, proliferation, and the expression of phenotype markers unique to T cell activation. These results suggested the potential of engineered bispecific antibodies, such as the construct described here, as prophylactic or therapeutic agents against HCMV reactivation and infection.

The Effects of Graphene Stacking on the Performance of Methane Sensor: A First-Principles Study on the Adsorption, Band Gap and Doping of Graphene.

The effects of graphene stacking are investigated by comparing the results of methane adsorption energy, electronic performance, and the doping feasibility of five dopants (i.e., B, N, Al, Si, and P) via first-principles theory. Both zigzag and armchair graphenes are considered. It is found that the zigzag graphene with Bernal stacking has the largest adsorption energy on methane, while the armchair graphene with Order stacking is opposite. In addition, both the Order and Bernal stacked graphenes possess a positive linear relationship between adsorption energy and layer number. Furthermore, they always have larger adsorption energy in zigzag graphene. For electronic properties, the results show that the stacking effects on band gap are significant, but it does not cause big changes to band structure and density of states. In the comparison of distance, the average interlamellar spacing of the Order stacked graphene is the largest. Moreover, the adsorption effect is the result of the interactions between graphene and methane combined with the change of graphene's structure. Lastly, the armchair graphene with Order stacking possesses the lowest formation energy in these five dopants. It could be the best choice for doping to improve the methane adsorption.

Trastuzumab triggers phagocytic killing of high HER2 cancer cells in vitro and in vivo by interaction with Fcγ receptors on macrophages.

Trastuzumab has been used for the treatment of HER2-overexpressing breast cancer for more than a decade, but the mechanisms of action for the therapy are still being actively investigated. Ab-dependent cell-mediated cytotoxicity mediated by NK cells is well recognized as one of the key mechanisms of action for trastuzumab, but trastuzumab-mediated Ab-dependent cellular phagocytosis (ADCP) has not been established. In this study, we demonstrate that macrophages, by way of phagocytic engulfment, can mediate ADCP and cancer cell killing in the presence of trastuzumab. Increased infiltration of macrophages in the tumor tissue was associated with enhanced efficacy of trastuzumab whereas depletion of macrophages resulted in reduced antitumor efficacy in mouse xenograft tumor models. Among the four mouse FcγRs, FcγRIV exhibits the strongest binding affinity to trastuzumab. Knockdown of FcγRIV in mouse macrophages reduced cancer cell killing and ADCP activity triggered by trastuzumab. Consistently, an upregulation of FcγRIV expression by IFN-γ triggered an increased ADCP activity by trastuzumab. In an analogous fashion, IFN-γ priming of human macrophages increased the expression of FcγRIII, the ortholog of murine FcγRIV, and increased trastuzumab-mediated cancer cell killing. Thus, in two independent systems, the results indicated that activation of macrophages in combination with trastuzumab can serve as a therapeutic strategy for treating high HER2 breast cancer by boosting ADCP killing of cancer cells.

Degradation modeling of mid-power white-light LEDs by using Wiener process.

The IES standard TM-21-11 provides a guideline for lifetime prediction of LED devices. As it uses average normalized lumen maintenance data and performs non-linear regression for lifetime modeling, it cannot capture dynamic and random variation of the degradation process of LED devices. In addition, this method cannot capture the failure distribution, although it is much more relevant in reliability analysis. Furthermore, the TM-21-11 only considers lumen maintenance for lifetime prediction. Color shift, as another important performance characteristic of LED devices, may also render significant degradation during service life, even though the lumen maintenance has not reached the critical threshold. In this study, a modified Wiener process has been employed for the modeling of the degradation of LED devices. By using this method, dynamic and random variations, as well as the non-linear degradation behavior of LED devices, can be easily accounted for. With a mild assumption, the parameter estimation accuracy has been improved by including more information into the likelihood function while neglecting the dependency between the random variables. As a consequence, the mean time to failure (MTTF) has been obtained and shows comparable result with IES TM-21-11 predictions, indicating the feasibility of the proposed method. Finally, the cumulative failure distribution was presented corresponding to different combinations of lumen maintenance and color shift. The results demonstrate that a joint failure distribution of LED devices could be modeled by simply considering their lumen maintenance and color shift as two independent variables.

Variants in the Atherogenic ALOX5AP, THBD, and KNG1 Genes Potentiate the Risk of Ischemic Stroke via a Genetic Main Effect and Epistatic Interactions in a Chinese Population.

BACKGROUND: Ischemic stroke (IS) is a multifactorial disease that displays a strong genetic predisposition. However, the genetic architecture of IS has yet to be fully elucidated. It was hypothesized that epistasis between genes in multiple atherothrombotic pathways may play a vital role in determining the susceptibility to IS. The aim of the present study was to investigate the contributions of the hypothesized genetic factors to IS and the interactions between these genetic factors in a Chinese population. METHODS: In this study, 351 cases with IS and 417 control subjects from a Chinese population were genotyped for single-nucleotide polymorphisms (SNPs) in 12 genes hypothesized to be involved in atherosclerosis, coagulation, and related pathways. We examined SNP main effects and epistatic interactions between these polymorphic loci. RESULTS: rs710446 of the KNG1 gene was associated with IS susceptibility based on an additive genetic model (rs710446: P = .012; odds ratio [OR], 1.247; 95% confidence interval [CI], 1.050-1.481) after adjusting for covariates. Furthermore, an epistatic interaction between the ALOX5AP, THBD, and KNG1 gene was also identified in association with stroke susceptibility (P < .001 after 1000 permutations). Based on the chi-squared test, the OR of the high-risk combination of the three-locus model increased the risk of IS by 2.53-fold (95% CI, 1.60-4.01; P < .0001). CONCLUSIONS: Our findings support the association of the epistatic interactions of ALOX5AP, THBD, and KNG1 and present novel evidence for the main effect of KNG1 gene on IS susceptibility, suggesting a modulation of stroke risk by a genetic main effect and gene-gene interactions.

[Genotype study on hepatitis C among entry foreigners in China].

OBJECTIVE: To monitor the the genotype and subgenotype c of hepatitis C among the immigrations. To identify the new genotype and trace the transmission. METHODS: From 2009 to 2013, 235 positive Anti-HCV samples were collected from Sichuan, Liaoning, Guangdong, Shenzhen and Yunnan ITHC. Specific PCR primers were used to amplify the HCV Core, then the PCR products were sequenced by genetic analyzer. The genotypes were identified by aligning the GenBank reference sequences and constructing the phylogenetic tree of Core. RESULTS: One hundred and twenty-nine samples showed HCV-RNA positive (54.9%) in 235 samples which were anti-HCV positive. We detected six kinds of genotypes in 115 cases of sequncing successfully, of which 72 cases of genotype 1 (G1, 62.6%), followed by G3 (18.2%), G2 (9.6%), G4 (6%), G6 (2.6%) and G5 (0.9%). Genotype 1b was the most common subtype, accounting for 47% of all infections. The phylogenetic tress indicated the HCV 4 strains in immigrations had high affinity with that in Egypt and Europe, while HCV 6 strains closed with that in China. CONCLUSIONS: HCV 1b is the advantage of popular genotype in HCV carriers. Subtype 4 may be a possible new genotype transmited into China. The immigrations may be the sources of new genotype of HCV.

Engagement of immune effector cells by trastuzumab induces HER2/ERBB2 downregulation in cancer cells through STAT1 activation.

INTRODUCTION: Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer for more than a decade. However, reports on the involvement of HER2 downregulation in trastuzumab's mechanism of action are inconsistent. The aim of this study is to investigate if the dependence of trastuzumab-mediated cancer cell HER2 downregulation on immune effector cells represents a novel mechanism of action for trastuzumab. METHODS: HER2 expression was evaluated by Western blotting, flow cytometry, and real-time polymerase chain reaction (PCR) in cell lysates from co-cultures of multiple cancer cell lines with peripheral blood mononuclear cells (PBMCs) in the presence or absence of trastuzumab. The engagement of immune cells by trastuzumab through Fc gamma receptors (FcγRs) was tested using three trastuzumab variants with compromised or no Fc (fragment crystallizable) functions and FcγRs blocking experiments. The engagement of immune cells by trastuzumab in HER2 downregulation was also evaluated in in vivo mouse xenograft tumor models. RESULTS: HER2 downregulation of cancer cells by trastuzumab occurred only when trastuzumab was actively engaged with immune cells and cancer cells, as demonstrated consistently in co-cultures of cancer cell lines with PBMCs and in vivo mouse xenograft tumor models. We further demonstrated that HER2 downregulation in cancer cells by immune-cell-engaged trastuzumab was at the transcriptional level, not through the HER2 degradation pathway. Activation of signal transducer and activator of transcription 1 (STAT1) in cancer cells by the increased interferon gamma (IFN-γ) production in immune cells played an important role in downregulating HER2 in cancer cells upon engagement of immune cells by trastuzumab. Furthermore, HER2 downregulation in cancer cells induced by trastuzumab engagement of immune cells was correlated with the antibody's antitumor efficacy in vivo. CONCLUSIONS: This study reveals that engagement of immune effector cells by trastuzumab induces HER2 downregulation in HER2-expressing cancer cells, which represents a new function of immune cells in trastuzumab-mediated antitumor efficacy and serves as a novel mechanism of action for trastuzumab. Our results imply that HER2 downregulation in cancer cells treated by trastuzumab may predict active engagement of immune effector cells in tumor microenvironment.

Erratum: Gut microbiota composition is associated with the efficacy of Delta-24-RGDOX in malignant gliomas.

[This corrects the article DOI: 10.1016/j.omton.2024.200787.].

Gut microbiota composition is associated with the efficacy of Delta-24-RGDOX in malignant gliomas.

Glioblastoma, the most common primary brain tumor, has a 6.8% survival rate 5 years post diagnosis. Our team developed an oncolytic adenovirus with an OX-40L expression cassette named Delta-24-RGDOX. While studies have revealed the interaction between the gut microbiota and immunotherapy agents, there are no studies linking the gut microbiota with viroimmunotherapy efficacy. We hypothesize that gut bacterial signatures will be associated with oncolytic viral therapy efficacy. To test this hypothesis, we evaluated the changes in gut microbiota in two mouse cohorts: (1) GSC-005 glioblastoma-bearing mice treated orally with indoximod, an immunotherapeutic agent, or with Delta-24-RGDOX by intratumoral injection and (2) a mouse cohort harboring GL261-5 tumors used to mechanistically evaluate the importance of CD4+ T cells in relation to viroimmunotherapy efficacy. Microbiota assessment indicated significant differences in the structure of the gut bacterial communities in viroimmunotherapy-treated animals with higher survival compared with control or indoximod-treated animals. Moreover, viroimmunotherapy-treated mice with prolonged survival had a higher abundance of Bifidobacterium. The CD4+ T cell depletion was associated with gut dysbiosis, lower mouse survival, and lower antitumor efficacy of the therapy. These findings suggest that microbiota modulation along the gut-glioma axis contributes to the clinical efficacy and patient survival of viroimmunotherapy treated animals.

Fc gamma receptors promote antibody-induced LILRB4 internalization and immune regulation of monocytic AML.

The immune checkpoint leukocyte immunoglobulin-like receptor B4 (LILRB4) is found specifically on the cell surface of acute monocytic leukemia (monocytic AML), an aggressive and common subtype of AML. We have developed a humanized monoclonal IgG1 LILRB4-blocking antibody (h128-3), which improved immune regulation but reduced cell surface expression of LILRB4 in monocytic AML models by 40-60%. Interestingly, most of this effect was neutralized by mutation of the Fc region of the antibody (h128-3/N297A), which prevents interaction with Fc gamma receptors (FcγRs). This suggested that there is FcγR-dependent antigenic modulation underlying h128-3's effects, a mechanism known to alter the function of antibodies targeting B-cell malignancies. We disrupted the Fc-FcγR interaction pharmacologically and with stable CRISPR-Cas9-mediated genetic knockout of FcγRs in monocytic AML cell lines to investigate the role of FcγR-dependent antigenic modulation in the regulation of LILRB4 by h128-3. When FcγRI is inhibited or removed from the surface of monocytic AML cells, h128-3 cannot optimally perform its blocking function, resulting in activation of the LILRB4 inhibitory receptor and leading to a 15-25% decrease in T-cell-mediated cytotoxicity in vitro. In the absence of FcγRI, scaffolding by FcγRIIa allows h128-3 to maintain LILRB4-blocking function. Here we define a FcγR-dependent antigenic modulation mechanism underlying the function of an immunoreceptor blocking antibody for the first time in myeloid malignancy. This research will facilitate the development of safe, precision-targeted antibody therapeutics in myeloid malignancies with greater potency and efficacy.