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A preprint by Xu et al. shows that MHC-pseudotyped retroviruses can reprogramme, activate and expand tumour-specific T cell populations in vivo.

A preprint by Xu et al. shows that MHC-pseudotyped retroviruses can reprogramme, activate and expand tumour-specific T cell populations in vivo.

ABSTRACT Prevention of robust severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in nasal turbinate (NT) requires in vivo evaluation of IgA neutralizing antibodies. Here, we report the efficacy of receptor binding domain (RBD)-specific monomeric B8-mIgA1 and B8-mIgA2, and dimeric B8-dIgA1, B8-dIgA2 and TH335-dIgA1 against intranasal SARS-CoV-2 challenge in Syrian hamsters. These antibodies exhibited comparable neutralization potency against authentic virus by competing with human angiotensin converting enzyme-2 (ACE2) receptor for RBD binding. While reducing viral loads in lungs significantly, prophylactic intranasal B8-dIgA unexpectedly led to high amount of infectious viruses and extended damage in NT compared to controls. Mechanistically, B8-dIgA failed to inhibit SARS-CoV-2 cell-to-cell transmission, but was hijacked by the virus through dendritic cell-mediated trans-infection of NT epithelia leading to robust nasal infection. Cryo-EM further revealed B8 as a class II antibody binding trimeric RBDs in 3-up or 2-up/1-down conformation. Neutralizing dIgA, therefore, may engage an unexpected mode of SARS-CoV-2 nasal infection and injury.

Prevention of robust severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in nasal turbinate (NT) requires evaluation of IgA neutralizing antibodies. Here, we report the efficacy of receptor binding domain (RBD)-specific monomeric B8-mIgA1 and B8-mIgA2, and dimeric B8-dIgA1, B8-dIgA2 and TH335-dIgA1 against intranasal SARS-CoV-2 challenge in Syrian hamsters. These antibodies exhibited comparable neutralization potency against authentic virus by competing with human angiotensin converting enzyme-2 (ACE2) receptor for RBD binding. While reducing viral loads in lungs significantly, prophylactic intranasal B8-dIgA unexpectedly led to high amount of infectious viruses and extended damage in NT compared to controls. Mechanistically, B8-dIgA failed to inhibit SARS-CoV-2 cell-to-cell transmission, but was hijacked by the virus through dendritic cell-mediated trans-infection of NT epithelia leading to robust nasal infection. Cryo-EM further revealed B8 as a class II antibody binding trimeric RBDs in 3-up or 2-up/1-down conformation. Neutralizing dIgA, therefore, may engage an unexpected mode of SARS-CoV-2 nasal infection and injury.

Robust severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in nasal turbinate (NT) accounts for high viral transmissibility, yet whether neutralizing IgA antibodies can control it remains unknown. Here, we evaluated receptor binding domain (RBD)-specific monomeric B8-mIgA1 and B8-mIgA2, and dimeric B8-dIgA1 and B8-dIgA2 against intranasal SARS-CoV-2 challenge in Syrian hamsters. These antibodies exhibited comparably potent neutralization against authentic virus by competing with human angiotensin converting enzyme-2 (ACE2) receptor for RBD binding. While reducing viruses in lungs, pre-exposure intranasal B8-dIgA1 or B8-dIgA2 led to 81-fold more infectious viruses and severer damage in NT than placebo. Virus-bound B8-dIgA1 and B8-dIgA2 could engage CD209 as an alternative receptor for entry into ACE2-negative cells and allowed viral cell-to-cell transmission. Cryo-EM revealed B8 as a class II neutralizing antibody binding trimeric RBDs in 3-up or 2-up/1-down conformation. Therefore, RBD-specific neutralizing dIgA engages an unexpected action for enhanced SARS-CoV-2 nasal infection and injury in Syrian hamsters. Competing Interest Statement J.F.W.C. has received travel grants from Pfizer Corporation Hong Kong and Astellas Pharma Hong Kong Corporation Limited and was an invited speaker for Gilead Sciences Hong Kong Limited and Luminex Corporation. The funding sources had no role in study design, data collection, analysis or interpretation or writing of the report. The other authors declare no conflicts of interest except for a provisional patent application filed for human monoclonal antibodies generated in our laboratory.

Emerging evidence suggests that cancer cells may disseminate early, prior to the formation of traditional macro-metastases. However, the mechanisms underlying the seeding and transition of early disseminated cancer cells (DCCs) into metastatic tumors remain poorly understood. Through single-cell RNA sequencing, we show that early lung DCCs from esophageal squamous cell carcinoma (ESCC) exhibit a trophoblast-like ‘tumor implantation’ phenotype, which enhances their dissemination and supports metastatic growth. Notably, ESCC cells overexpressing GPRC5A demonstrate improved implantation and persistence, resulting in macro-metastases in the lungs. Clinically, elevated GPRC5A level is associated with poorer outcomes in a cohort of 148 ESCC patients. Mechanistically, GPRC5A is found to potentially interact with WWP1, facilitating the polyubiquitination and degradation of LATS1, thereby activating YAP1 signaling pathways essential for metastasis. Importantly, targeting YAP1 axis with CA3 or TED-347 significantly diminishes early implantation and macro-metastases. Thus, the GPRC5A/WWP1/LATS1/YAP1 pathway represents a crucial target for therapeutic intervention in ESCC lung metastases. The mechanisms allowing early disseminated cancer cells colonize other tissues remain largely unknown. Here, authors show that GPRC5A axis drives esophageal squamous cell carcinoma lung seeding and metastasis, in a mechanism resembling trophoblast behavior during embryo implantation.

The new entry inhibitor eCD4-Ig, consisting of the immunoadhesin form of CD4 (CD4-Ig) fused to a small CCR5-mimetic sulfopeptide, avidly binds two highly conserved sites of the HIV-1 Env protein; the inhibitor has high potency and breadth and can neutralize 100% of a diverse panel of neutralization-resistant HIV-1 viruses, and when delivered to macaques using an adeno-associated virus vector, it can provide effective long-term protection from multiple challenges with simian/human immunodeficiency virus. HIV-1 entry inhibitors with vaccine-like action This study describes a novel class of highly potent HIV-1 entry inhibitors that can be delivered with a gene-therapy vector to provide an effective alternative to conventional vaccines for HIV-1. To enter cells, HIV-1 first binds its cellular receptor CD4, then the co-receptor CCR5 or CXCR4 The new entry inhibitor consists of the immunoadhesin CD4-Ig fused to a sulfopeptide mimicking CCR5. This fusion, called eCD4-Ig, avidly binds the Env protein of HIV-1 and irreversibly inactivates it. Michael Farzan and colleagues show that this inhibitor has exceptional potency and breadth and can neutralize 100% of a diverse panel of neutralization-resistant HIV-1. When delivered to macaques using an adeno-associated virus, it can protect them from multiple challenges with virus. Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs) 1 , 2 . However, even the best bNAbs neutralize 10–50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC 80 ) > 5 μg ml −1 ), suggesting that high concentrations of these antibodies would be necessary to achieve general protection 3 , 4 , 5 , 6 . Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC 50 ) < 0.05 μg ml −1 ). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17–77 μg ml −1 of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.

BackgroundGlioblastomas (GBMs) are a prevalent form of brain tumor with median overall survival of 1-1.5 years, and inevitable recurrence after initial surgical resection and chemotherapy. Less than half of patients are eligible for surgery at recurrence.1 In many other cancers, checkpoint immunotherapies are efficacious, but GBMs resist treatment. Multiple resistance mechanisms may be at play and overcoming them is essential to improve immunotherapy response. The high heterogeneity of GBM, both in cellular phenotype and immune landscape, likely contributes to resistance. Although the GBM tumor-immune transcriptome is well-studied, spatial organization is an open frontier.MethodsSpatial transcriptomic samples were analyzed from a two-arm randomized trial for recurrent GBM patients (NCT04201873). One arm received neoadjuvant and adjuvant PD-1 mAb (“neoadjuvant” group), while the other received placebo (“placebo” group). Both groups received adjuvant autologous tumor lysate-pulsed DC vaccination. Tissue samples (N=10) were taken from on-study surgical resection, with 4 patients in the neoadjuvant group, 6 in placebo. The Visium spatial assay was applied to produce 3,140 +/- 969 transcriptomic “spots” per sample, 31,395 in total. Gene signature analysis quantified each spot’s tumor-immune composition. Signatures were obtained from MSigDB Hallmarks, ImSig,2 and Neftel et. al.3 AUCell4 was used to score signatures at each spot.ResultsAnalysis of glioma subtype signatures showed mesenchymal scores (MES1 and MES2) highly correlated [Pearson coefs. > 0.77], while astrocyte (AC), oligodendrocyte precursor (OPC), and neural precursor (NPC1 and NPC2) scores formed a second correlated group [Pearson coefs. > 0.5]. There was no discernable difference in correlation structure between neoadjuvant and placebo patients.MES1-high spots had a characteristic signature of high macrophage, hypoxia, angiogenesis, glycolysis, interferon-gamma response, TGF-beta, and TNF-alpha scores [Pearson coefs. > 0.5]. AC, OPC and NPC-high spots correlated weakly to immune and vascular signatures [Pearson coefs. < 0.35]. Microglia did not correlate highly to other scores [Pearson coefs < 0.35].Differential expression showed negative log fold-change (logFC) in glioma subtype scores for neoadjuvant patients, for all types except NPC2 [Wilcox tests, p < 0.001]. Negative logFC was observed for macrophages, TNF-alpha, hypoxia, and proliferation, but positive logFC for T-cells and microglia.ConclusionsSpatial-transcriptomic analysis suggests that patients treated with neoadjuvant immunotherapy have lower mesenchymal subtype scores, with lower proliferation, but higher T-cell scores. Subsequent analysis will relate neoadjuvant immunotherapy with spatial heterogeneity of T-cells, myeloid subtypes, glioma subtypes, and vascularization, to understand resistance mechanisms.Trial RegistrationNCT04201873ReferencesBirzu C, French P, Caccese M, Cerretti G, Idbaih A, Zagonel V, & Lombardi G. Recurrent glioblastoma: from molecular landscape to new treatment perspectives. Cancers. 2020;13(1):47.Ajit J Nirmal, Tim Regan, Barbara B Shih, David A Hume, Andrew H Sims and Tom C. Immune Cell Gene Signatures for Profiling the Microenvironment of Solid Tumors. Freeman Cancer Immunol Res. 2018;6(11):1388–1400; DOI: 10.1158/2326-6066.CIR-18-0342Neftel C, Laffy, J, Filbin, MG, HaraT, Shore ME, Rahme GJ, and Suvà, ML (2019). An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell, 178(4), 835–849.Aibar S, Bravo Gonzalez-Blas C, Moerman T, Huynh-Thu V, Imrichova H, Hulselmans G, Rambow F, Marine J, Geurts P, Aerts J, van den Oord J, Kalender Atak Z, Wouters J, Aerts S (2017). SCENIC: Single-Cell Regulatory Network Inference And Clustering. Nature Methods. 2017;14:1083–1086.

We provide a lower bound for the efficiency of polarization or coherence transfer between quantized states under unitary transformations. Mathematically the problem is the determination of the $C$-numerical radius of $A$ for certain nilpotent matrices $C$ and $A$. The presented lower bound is conjectured to be exact as it coincides with numerical data provided in [U. Helmke et al., J. Global Optim., 23 (2002), pp. 283-308].