Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/ B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.
Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT-mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNg-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.
B7-H1 is an immunoglobulin-like immune suppressive molecule broadly detectable on the majority of human and rodent cancers, and its functions have been attributed to delivering an inhibitory signal to its counter-receptor programmed death-1 (PD-1) on T cells. Here we report that B7-H1 on cancer cells receives a signal from PD-1 to rapidly induce resistance against T cell-mediated killing because crippling signaling capacity of B7-H1 but not PD-1 ablates this resistance. Importantly, loss of B7-H1 signaling is accompanied by increased susceptibility to immune-mediated tumoricidal activity. In addition to resistance against T-cell destruction, B7-H1 ؉ cancer cells also become refractory to apoptosis in- IntroductionCancer cells display altered surface molecular signatures that distinguish them quantitatively and qualitatively from their normal derivatives. These modifications in receptor and ligand expression commonly facilitate tumor growth and progression or to evasion of host defense mechanisms. 1,2 For example, some tumor cells down-regulate their cell surface major histocompatibility complex (MHC), which is required for recognition by tumor antigen-specific T lymphocytes. 3 As a result, these tumor cells become less recognizable by the immune system and more resistant to immunemediated destruction. Another example is that during progression, cancer cells frequently overexpress proteases and modify glycosylation of cell surface proteins that are normally involved in tissue repair, remodeling, and homeostasis to facilitate invasion and metastasis. 4,5 In general, these modifications in cell membrane ligands and receptors regulate interactions between tumor cells and nontransformed cells in the microenvironment in a fashion that enhances tumor growth, invasion, and immune resistance.We previously identified an immunoglobulin (Ig)-like molecule termed B7-H1, 6 which is either constitutively or inducibly expressed by the majority of human and rodent cancer cells. 7,8 Ample evidence demonstrates that B7-H1 acts as a ligand for the receptor programmed death-1 (PD-1) to deliver an inhibitory signal to T cells, leading to inhibition of immune responses. 9 The mechanisms underlying B7-H1/PD-1-mediated suppression include induction of apoptosis, anergy, unresponsiveness, and exhaustion of T cells. 7, Interaction between B7-H1 and PD-1 is also shown to participate in the suppression of autoimmune diseases and transplantation rejection in animal models. 15-18. A recent study suggests that B7-H1, in addition to PD-1, also binds B7-1 (CD80) on T cells to inhibit their activation. 19 We and others have observed that B7-H1 ϩ tumor cells are much more resistant to CD8 ϩ cytolytic T cell (CTL)-mediated destruction in vitro than their B7-H1-negative parental cells, and this resistance is correlated with decreased efficacy of immunotherapy in mouse tumor models.  Ablation of B7-H1 and PD-1 interaction by neutralizing antibodies could restore CTL-mediated lysis of tumor cells in vitro, suggesting ...
Majority of cancer cells upregulate co-inhibitory molecule B7-H1 which confers resistance to anti-tumor immunity, allowing cancers to escape from host immune surveillance. We addressed the molecular mechanism underlying the regulation of cancer-associated B7-H1 expression in response to interferon-c (IFN-c). Using promoter constructs in luciferase assay, the region between 202 and 320 bp from the translational start site is responsible for B7-H1 expression. Electrophoretic mobility shift assay, site-directed mutagenesis and knockdown experiment using siRNA revealed that interferon regulatory factor-1 (IRF-1) is primarily responsible for the constitutive B7-H1 expression as well as for the IFN-c-mediated B7-H1 upregulation in a human lung cancer cell line A549. Additionally, AG490, a Janus activated kinase/signal transducer and activator of transcription inhibitor, greatly abolished the responsiveness of A549 cells to IFN-c by reducing the IRF-1 transcription. Our findings support a critical role of IRF-1 in the regulation of constitutive and IFN-c-induced expression of B7-H1 in cancer cells.
Purpose Results from the first-in-human phase I trial of the anti-programmed death-1 (PD-1) antibody BMS-936558 in patients with treatment-refractory solid tumors, including safety, tolerability, pharmacodynamics, and immunologic correlates, have been previously reported. Here, we provide long-term follow-up on three patients from that trial who sustained objective tumor regressions off therapy, and test the hypothesis that re-induction therapy for late tumor recurrence can be effective. Patients and methods Three patients with colorectal cancer, renal cell cancer, and melanoma achieved objective responses on an intermittent dosing regimen of BMS-936558. Following cessation of therapy, patients were followed for over 3 years. A patient with melanoma who experienced a prolonged partial regression followed by tumor recurrence received re-induction therapy. Results A patient with colorectal cancer experienced a complete response which is ongoing after 3 years. A patient with renal cell cancer experienced a partial response lasting 3 years off therapy, which converted to a complete response which is ongoing at 12 months. A patient with melanoma achieved a partial response that was stable for 16 months off therapy; recurrent disease was successfully treated with re-induction anti-PD-1 therapy. Conclusion These data represent the most prolonged observation to date of patients with solid tumors responding to anti-PD-1 immunotherapy and the first report of successful re-induction therapy following delayed tumor progression. They underscore the potential for immune checkpoint blockade with anti-PD-1 to reset the equilibrium between tumor and the host immune system.
Aggregation of polar merocyanine dyes has been identified as an important problem in the fabrication of organic materials for photonic applications. In this work, a series of merocyanine dyes is synthesized, and their aggregation is investigated by a combination of several experimental techniques to reveal structure-property relationships. These studies provide clear evidence for the formation of centrosymmetric dimers for all investigated merocyanines in concentrated solution and in the solid state. The thermodynamics of dimerization in liquid solution is studied by concentration-dependent permittivity measurements, UV-vis spectroscopy, and electrooptical absorption experiments. A centrosymmetric dimer structure with antiparallel ordering of the dipole moments is observed in solution by 2D NMR spectroscopy as well as in the solid state by X-ray crystallography and interpreted in terms of dipolar and pi-pi interactions. The optical properties of the dimer aggregates are satisfactorily explained by an excitonic coupling model. The effect of an external electric field on the dimerization equilibrium is considered and quantitatively determined by electrooptical absorption measurements. Implications of the observed findings on the design of nonlinear optical and photorefractive materials are discussed.
Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a “shield” in front of the catalytic dyad to effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.
Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment (TME) is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death 1 (PD-1) and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a GM-CSF secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared to PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8+ T lymphocytes and tumor-specific interferon-γ production of CD8+ T cells in the TME. Immunosuppressive pathways, including regulatory T cells (Tregs) and CTLA-4 expression on T cells were overcome by the addition of vaccine and low dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.
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