LAG3 is an important immune checkpoint with relevance in cancer, infectious disease and autoimmunity. However, despite LAG3's role in immune exhaustion and the great potential of LAG3 inhibition as treatment, much remains unknown about its biology, particularly its mechanism of action. This review describes the knowns, unknowns and controversies surrounding LAG3. This includes examination of how LAG3 is regulated transcriptionally and post-translationally by endocytosis and proteolytic cleavage. We also discuss the interactions of LAG3 with its ligands and the purpose thereof. Finally, we review LAG3's mechanism of action, including the roles of LAG3 intracellular motifs and the lack of a role for CD4 competition. Overall, understanding the biology of LAG3 can provide greater insight on LAG3 function, which may broaden the appreciation for LAG3's role in disease and potentially aid in the development of targeted therapies.Agonistic monoclonal antibodies (mAbs) targeting the co-stimulatory receptor 4-1BB are among the most effective immunotherapeutic agents across pre-clinical cancer models. However, clinical development of full-length 4-1BB agonistic mAbs, has been hampered by dose-limiting liver toxicity. We have previously developed an EGFR-targeted 4-1BB-agonistic trimerbody (1D8N/CEGa1) that induces potent anti-tumor immunity without systemic toxicity, in immunocompetent mice bearing murine colorectal carcinoma cells expressing human EGFR. Here, we study the impact of human EGFR expression on mouse liver in the toxicity profile of 1D8N/CEGa1. Systemic administration of IgG-based anti-4-1BB agonist resulted in nonspecific immune stimulation and hepatotoxicity in a liver-specific human EGFR-transgenic immunocompetent mouse, whereas in 1D8N/CEGa1-treated mice no such immune-related adverse effects were observed. Collectively, these data support the role of FcγR interactions in the major off-tumor toxicities associated with IgG-based 4-1BB agonists and further validate the safety profile of EGFR-targeted Fc-less 4-1BB-agonistic trimerbodies in systemic cancer immunotherapy protocols.Allogeneic hematopoietic cell transplantation (allo-HCT) is an efficacious and frequently the only treatment option for some hematological malignances. However, it often faces severe morbidities and/or mortalities due to graft versus host disease, and the severity of the conditioning regiment needed, that result in toxicity-related issues poorly tolerable for some patients.  https://www.selleckchem.com/TGF-beta.html  These shortcomings have led to the development of less aggressive alternatives like non-myeloablative (NMAC) or reduced-intensity conditioning regiments (RIC). However, these approaches tend to have an increase of cancer relapse and limited persistence of donor-specific chimerism. Thus, strategies that lead towards an accelerated and more durable donor engraftment are still needed. Here, we took advantage of the ability of host-derived unlicensed NK (UnLicNK) cells to favor donor cell engraftment during myeloablative allo-HCT, and evaluated if the adoptive transfer of this cell type can improve donor chimerism in NAMC settings. Indeed, the infusion of these cells significantly increased mixed chimerism in a sublethal allo-HCT mouse model, resulting in a more sustainable donor cell engraftment when compared to the administration of licensed NK cells or HCT controls. We observed an overall increase in the total number and proportion of donor B, NK and myeloid cells after UnLicNK cell infusion. Additionally, the extension and durability of donor chimerism was similar to the one obtained after the tolerogenic Tregs infusion. These results serve as the needed bases for the implementation of the adoptive transfer of UnLicNK cells to upgrade NMAC protocols and enhance allogeneic engraftment during HCT.The Toll pathway plays an important role in defense against infection of various pathogenic microorganisms, including viruses. However, current understanding of Toll pathway was mainly restricted in mammal and some model insects such as Drosophila and mosquitoes. Whether plant viruses can also activate the Toll signaling pathway in vector insects is still unknown. In this study, using rice stripe virus (RSV) and its insect vector (small brown planthopper, Laodelphax striatellus) as a model, we found that the Toll pathway was activated upon RSV infection. In comparison of viruliferous and non-viruliferous planthoppers, we found that four Toll pathway core genes (Toll, Tube, MyD88, and Dorsal) were upregulated in viruliferous planthoppers. When the planthoppers infected with RSV, the expressions of Toll and MyD88 were rapidly upregulated at the early stage (1 and 3 days post-infection), whereas Dorsal was upregulated at the late stage (9 days post-infection). Furthermore, induction of Toll pathway was initiated by interaction between a Toll receptor and RSV nucleocapsid protein (NP). Knockdown of Toll increased the proliferation of RSV in vector insect, and the dsToll-treated insects exhibited higher mortality than that of dsGFP-treated ones. Our results provide the first evidence that the Toll signaling pathway of an insect vector is potentially activated through the direct interaction between Toll receptor and a protein encoded by a plant virus, indicating that Toll immune pathway is an important strategy against plant virus infection in an insect vector.
  There is no study accessible now assessing the prognostic aspect of radiomics for anti-PD-1 therapy for patients with HCC.
 
  The aim of this study was to develop and validate a radiomics nomogram by incorporating the pretreatment contrast-enhanced Computed tomography (CT) images and clinical risk factors to estimate the anti-PD-1 treatment efficacy in Hepatocellular Carcinoma (HCC) patients.
 
  A total of 58 patients with advanced HCC who were refractory to the standard first-line of therapy, and received PD-1 inhibitor treatment with Toripalimab, Camrelizumab, or Sintilimab from 1st January 2019 to 31 July 2020 were enrolled and divided into two sets randomly training set (n = 40) and validation set (n = 18). Radiomics features were extracted from non-enhanced and contrast-enhanced CT scans and selected by using the least absolute shrinkage and selection operator (LASSO) method. Finally, a radiomics nomogram was developed based on by univariate and multivariate logistic regression analysis. The performance of the nomogram was evaluated by discrimination, calibration, and clinical utility.