Maspin is a tumour suppressor that inhibits breast cancer tumour metastasis in vivo

Maspin is a member of the serpin family of serine proteases and functions as a tumour suppressor. A study using a new syngeneic mouse model for breast cancer suggests that maspin can inhibit metastasis in vivo

Human cytomegalovirus latency-associated proteins elicit immune-suppressive IL-10 producing CD4⁺ T cells.

Human cytomegalovirus (HCMV) is a widely prevalent human herpesvirus, which, after primary infection, persists in the host for life. In healthy individuals, the virus is well controlled by the HCMV-specific T cell response. A key feature of this persistence, in the face of a normally robust host immune response, is the establishment of viral latency. In contrast to lytic infection, which is characterised by extensive viral gene expression and virus production, long-term latency in cells of the myeloid lineage is characterised by highly restricted expression of viral genes, including UL138 and LUNA. Here we report that both UL138 and LUNA-specific T cells were detectable directly ex vivo in healthy HCMV seropositive subjects and that this response is principally CD4⁺ T cell mediated. These UL138-specific CD4⁺ T cells are able to mediate MHC class II restricted cytotoxicity and, importantly, show IFNγ effector function in the context of both lytic and latent infection. Furthermore, in contrast to CDCD4⁺ T cells specific to antigens expressed solely during lytic infection, both the UL138 and LUNA-specific CD4⁺ T cell responses included CD4⁺ T cells that secreted the immunosuppressive cytokine cIL-10. We also show that cIL-10 expressing CD4⁺ T-cells are directed against latently expressed US28 and UL111A. Taken together, our data show that latency-associated gene products of HCMV generate CD4⁺ T cell responses in vivo, which are able to elicit effector function in response to both lytic and latently infected cells. Importantly and in contrast to CD4⁺ T cell populations, which recognise antigens solely expressed during lytic infection, include a subset of cells that secrete the immunosuppressive cytokine cIL-10. This suggests that HCMV skews the T cell responses to latency-associated antigens to one that is overall suppressive in order to sustain latent carriage in vivo

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity

Human Cytomegalovirus Fcγ Binding Proteins gp34 and gp68 Antagonize Fcγ Receptors I, II and III

Human cytomegalovirus (HCMV) establishes lifelong infection with recurrent episodes of virus production and shedding despite the presence of adaptive immunological memory responses including HCMV immune immunoglobulin G (IgG). Very little is known how HCMV evades from humoral and cellular IgG-dependent immune responses, the latter being executed by cells expressing surface receptors for the Fc domain of IgG (FcγRs). Remarkably, HCMV expresses the RL11-encoded gp34 and UL119-118-encoded gp68 type I transmembrane glycoproteins which bind Fcγ with nanomolar affinity. Using a newly developed FcγR activation assay, we tested if the HCMV-encoded Fcγ binding proteins (HCMV FcγRs) interfere with individual host FcγRs. In absence of gp34 or/and gp68, HCMV elicited a much stronger activation of FcγRIIIA/CD16, FcγRIIA/CD32A and FcγRI/CD64 by polyclonal HCMV-immune IgG as compared to wildtype HCMV. gp34 and gp68 co-expression culminates in the late phase of HCMV replication coinciding with the emergence of surface HCMV antigens triggering FcγRIII/CD16 responses by polyclonal HCMV-immune IgG. The gp34- and gp68-dependent inhibition of HCMV immune IgG was fully reproduced when testing the activation of primary human NK cells. Their broad antagonistic function towards FcγRIIIA, FcγRIIA and FcγRI activation was also recapitulated in a gain-of-function approach based on humanized monoclonal antibodies (trastuzumab, rituximab) and isotypes of different IgG subclasses. Surface immune-precipitation showed that both HCMV-encoded Fcγ binding proteins have the capacity to bind trastuzumab antibody-HER2 antigen complexes demonstrating simultaneous linkage of immune IgG with antigen and the HCMV inhibitors on the plasma membrane. Our studies reveal a novel strategy by which viral FcγRs can compete for immune complexes against various Fc receptors on immune cells, dampening their activation and antiviral immunity.DFG grant He 2526/6-2.European Commission grants QLRT-2001-01112 and MRTN-CT-2005-019248.Helmholtz Association through VISTRIE VH-VI-242.UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologí

PP01.10 A Randomized, Open-Label Phase 2 Study of the TORC 1/2 Inhibitor Sapanisertib in Relapsed/Refractory (R/R) NFE2L2 (NRF2)-Mutated and Wild-Type (WT) Squamous Non-Small Cell Lung Cancer (sqNSCLC)

Background: Activation of the transcription factor NRF2 increases the expression of genes that regulate defense against reactive oxygen species and cellular stress, which is implicated in tumorigenesis of several cancer types. NRF2 activation in tumor cells has also been found to accelerate metabolic inactivation of certain antitumor agents and decrease intracellular drug concentrations, promoting drug resistance and tumor growth. Aberrant activation of NRF2 results from gain-of-function mutations in NFE2L2 (the gene that encodes NRF2) or loss-of-function mutations in KEAP1 (a negative regulator of NRF2) leading to upregulated signaling through the mTOR pathway. This event occurs early in NSCLC tumorigenesis and is associated with poor prognosis in patients with metastatic sqNSCLC. sqNSCLC cell lines harboring NFE2L2 or KEAP1 mutations have demonstrated selective sensitivity to the dual TORC1/2 inhibitor sapanisertib, compared to TORC1-only inhibitors (Paik et al. ASCO 2020). In a phase 2 trial, single agent sapanisertib was well tolerated and led to an overall response rate (ORR) of 25%, disease control rate (DCR) of \u3e90%, and median progression-free survival (PFS) of 8.9 months in 12 patients with NFE2L2-mutated sqNSCLC (Paik et al. ASCO 2020). Preclinical data and encouraging early clinical activity formed the rationale for conducting this phase 2 study to evaluate the efficacy and further refine the dose of sapanisertib monotherapy in patients with R/R NFE2L2-mutant and wild-type (WT) sqNSCLC (NCT05275673). Methods: This multicenter, randomized, open-label study will enroll approximately 50 patients with histologically or cytologically documented stage IV sqNSCLC in 2 arms: NFE2L2-mutant cohort (Group A) or NFE2L2-WT cohort (Group B). Patients must have disease that progressed during or after prior systemic therapy for metastatic disease, including a platinum doublet and immune checkpoint inhibitor. Additional eligibility criteria include measurable disease per RECIST v1.1, and ECOG performance status 0-1. Study-eligible mutation in NFE2L2 or NFE2L2-WT status will be determined via next generation sequencing. Both Group A and Group B patients (NFE2L2-mutated) will be randomized to sapanisertib 3 mg once daily or 2 mg twice daily in 21-day cycles. The primary endpoints are investigator-assessed ORR per RECIST v1.1 and safety. Secondary endpoints are duration of response, PFS, and overall survival. Exploratory endpoints include PK/PD and biomarker analyses. Findings from this study will inform on the optimal dose/schedule and further confirm previously shown efficacy and safety of sapanisertib in patients with metastatic R/R NFE2L2-mutated sqNSCLC and evaluate its activity in NFE2L2-WT sqNSCLC

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