Explore the vast range of titles available.

Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and it is considered a potential next-generation cancer immunotherapy target in human therapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 and its relationship with other immune checkpoint molecules remain poorly understood. This is partly caused by the presence of non-conventional signaling motifs in its intracellular domain that are different from other conventional immunoregulatory signaling motifs but with similar inhibitory activities. Here we summarize the current understanding of LAG-3 signaling and its role in LAG-3 functions, from its mechanisms of action to clinical applications.

Programmed cell death-1 ligand-1 (PD-L1) overexpression in cancer cells accelerates tumor progression. PD-L1 possesses two main pro-oncogenic functions. First, PD-L1 is a strong immunosuppressive molecule that inactivates tumor-specific T cells by binding to the inhibitory receptor PD-1. Second, PD-L1 function relies on the delivery of intrinsic intracellular signals that enhance cancer cell survival, regulate stress responses and confer resistance toward pro-apoptotic stimuli, such as interferons. Here, we review the current knowledge on intracellular signal transduction pathways regulated by PD-L1, describe its associated signalosome and discuss potential combinations of targeted therapies against the signalosome with PD-L1/PD-1 blockade therapies.

The majority of lung cancer patients progressing from conventional therapies are refractory to PD‐L1/PD‐1 blockade monotherapy. Here, we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients, CD4 T cells possessed significant proliferative capacities, low co‐expression of PD‐1/LAG‐3 and were responsive to PD‐1 blockade ex vivo and in vivo . In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer‐specific T cells. Although proficient in cytokine production, CD4 T cells in these patients proliferated very poorly, strongly co‐upregulated PD‐1/LAG‐3, and were largely refractory to PD‐1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T‐cell proliferative dysfunctionality could be reverted by PD‐1/LAG‐3 co‐blockade. Patients with functional CD4 immunity and PD‐L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD‐L1/PD‐1 blockade therapy. Synopsis Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond. Functional systemic CD4 immunity is required for objective clinical responses to PD‐L1/PD‐1 blockade therapy in human lung cancer patients. Systemic memory CD4 T cells identify intrinsic non‐responder from potentially responder patients. 70% of patients with high baseline percentages of memory CD4 T cells and PD‐L1‐positive tumors respond to therapy. Proliferative CD4 dysfunctionality in non‐responder patients can be overcome by PD‐1/LAG‐3 co‐blockade. Graphical Abstract Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond.

PD-L1/PD-1 blockade immunotherapy has significantly improved treatment outcome for several cancer types compared to conventional cytotoxic therapies. However, the specific molecular and cellular mechanisms behind its efficacy are currently unclear. There is increasing evidence in murine models and in patients that unveil the key importance of systemic immunity to achieve clinical responses under several types of immunotherapy. Indeed, PD-L1/PD-1 blockade induces the expansion of systemic CD8+ PD-1+ T cell subpopulations which might be responsible for direct anti-tumor responses. However, the role of CD4+ T cells in PD-L1/PD-1 blockade-induced anti-tumor responses has been less documented. In this review we focus on the experimental data supporting the “often suspected” indispensable helper function of CD4 T cells towards CD8 effector anti-tumor responses in cancer; and particularly, we highlight the recently published studies uncovering the key contribution of systemic CD4 T cells to clinical efficacy in PD-L1/PD-1 blockade therapies. We conclude and propose that the presence of specific CD4 T cell memory subsets in peripheral blood before the initiation of treatments is a strong predictor of responses in non-small cell lung cancer patients. Therefore, development of new approaches to improve CD4 responses before PD-L1/PD-1 blockade therapy could be the solution to increase response rates and survival of patients.

Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation and antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With the approval of more ICIs, irAE prediction has become a key factor in improving patient survival and quality of life. Several biomarkers have been described as potential irAE predictors, some of them are already available for clinical use and others are under development; examples include circulating blood cell counts and ratios, T-cell expansion and diversification, cytokines, autoantibodies and autoantigens, serum and other biological fluid proteins, human leucocyte antigen genotypes, genetic variations and gene profiles, microRNAs, and the gastrointestinal microbiome. Nevertheless, it is difficult to generalize the application of irAE biomarkers based on the current evidence because most studies have been retrospective, time-limited and restricted to a specific type of cancer, irAE or ICI. Long-term prospective cohorts and real-life studies are needed to assess the predictive capacity of different potential irAE biomarkers, regardless of the ICI type, organ involved or cancer site.

AspH is an endoplasmic reticulum (ER) membrane-anchored 2-oxoglutarate oxygenase whose C-terminal oxygenase and tetratricopeptide repeat (TPR) domains present in the ER lumen. AspH catalyses hydroxylation of asparaginyl- and aspartyl-residues in epidermal growth factor-like domains (EGFDs). Here we report crystal structures of human AspH, with and without substrate, that reveal substantial conformational changes of the oxygenase and TPR domains during substrate binding. Fe(II)-binding by AspH is unusual, employing only two Fe(II)-binding ligands (His679/His725). Most EGFD structures adopt an established fold with a conserved Cys1–3, 2–4, 5–6 disulfide bonding pattern; an unexpected Cys3–4 disulfide bonding pattern is observed in AspH-EGFD substrate complexes, the catalytic relevance of which is supported by studies involving stable cyclic peptide substrate analogues and by effects of Ca(II) ions on activity. The results have implications for EGFD disulfide pattern processing in the ER and will enable medicinal chemistry efforts targeting human 2OG oxygenases. AspH catalyses hydroxylation of asparagine and aspartate residues in epidermal growth factor-like domains (EGFDs). Here, the authors present crystal structures of AspH with and without substrates and show that AspH uses EFGD substrates with a non-canonical disulfide pattern.

Viroporins are viral proteins with ion channel (IC) activity that play an important role in several processes, including virus replication and pathogenesis. While many coronaviruses (CoVs) encode two viroporins, severe acute respiratory syndrome CoV (SARS-CoV) encodes three: proteins 3a, E, and 8a. Additionally, proteins 3a and E have a PDZ-binding motif (PBM), which can potentially bind over 400 cellular proteins which contain a PDZ domain, making them potentially important for the control of cell function. In the present work, a comparative study of the functional motifs included within the SARS-CoV viroporins was performed, mostly focusing on the roles of the IC and PBM of E and 3a proteins. Our results showed that the full-length E and 3a proteins were required for maximal SARS-CoV replication and virulence, whereas viroporin 8a had only a minor impact on these activities. A virus missing both the E and 3a proteins was not viable, whereas the presence of either protein with a functional PBM restored virus viability. E protein IC activity and the presence of its PBM were necessary for virulence in mice. In contrast, the presence or absence of the homologous motifs in protein 3a did not influence virus pathogenicity. Therefore, dominance of the IC and PBM of protein E over those of protein 3a was demonstrated in the induction of pathogenesis in mice. IMPORTANCE Collectively, these results demonstrate key roles for the ion channel and PBM domains in optimal virus replication and pathogenesis and suggest that the viral viroporins and PBMs are suitable targets for antiviral therapy and for mutation in attenuated SARS-CoV vaccines. Collectively, these results demonstrate key roles for the ion channel and PBM domains in optimal virus replication and pathogenesis and suggest that the viral viroporins and PBMs are suitable targets for antiviral therapy and for mutation in attenuated SARS-CoV vaccines.

Cancer immunotherapies targeting immune checkpoints such as programmed cell-death protein 1 (PD-1) and its ligand programmed cell-death 1 ligand 1 (PD-L1), are revolutionizing cancer treatment and transforming the practice of medical oncology. However, despite all the recent successes of this type of immunotherapies, most patients are still refractory and present either intrinsic resistance or acquired resistance. Either way, this is a major clinical problem and one of the most significant challenges in oncology. Therefore, the identification of biomarkers to predict clinical responses or for patient stratification by probability of response has become a clinical necessity. However, the mechanisms leading to PD-L1/PD-1 blockade resistance are still poorly understood. A deeper understanding of the basic mechanisms underlying resistance to cancer immunotherapies will provide insight for further development of novel strategies designed to overcome resistance and treatment failure. Here we discuss some of the major molecular mechanisms of resistance to PD-L1/PD-1 immune checkpoint blockade and argue whether tumor intrinsic or extrinsic factors constitute main determinants of response and resistance.

Immunotherapies targeting the programmed cell death-1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1) pathway sparked a revolution in cancer treatment. These breakthrough therapies work by disrupting the interaction between PD-1—expressed on T cells—and its ligand PD-L1, commonly found on the surface of cancer cells. By using monoclonal antibodies to block this binding, the immune system is unleashed to fight cancer more effectively. However, PD-L1’s role extends far beyond immune evasion. When situated on cancer cells, PD-L1 transmits inhibitory signals through PD-1, silencing the effector functions of T cells. However, PD-L1 also engages in reverse signaling, also called intrinsic signaling, delivering intracellular instructions that contribute to cancer cell survival, even in the absence of PD-1 binding. This signaling cascade shields cancer cells from apoptosis, drives proliferation, regulates DNA damage responses, and even functions as a co-transcriptional transactivator, amplifying cancer’s ability to thrive. The intricate mechanisms behind PD-L1’s intrinsic signaling are under intense investigation. In this review, we provide a historical perspective on the discoveries leading to PD-L1’s structure, signaling motifs, and interacting partners, shedding light on its multifaceted roles and the promising therapeutic possibilities ahead.

Quantum gravity theories rely on a minimal measurable length for their formulations, which clashes with the classical formulation of the uncertainty principle and with Lorentz invariance from general relativity. These incompatibilities led to the development of the generalized uncertainty principle (GUP) from string theories and its various modifications. GUP and covariant formulations of the uncertainty principle are discussed, together with implications for space–time quantization.