Search results for "Tumor microenvironment."
showing 10 items of 307 documents
Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery
2020
Cathepsin S (CatS) is a secreted cysteine protease that cleaves certain extracellular matrix proteins, regulates antigen presentation in antigen-presenting cells (APC), and promotes M2-type macrophage and dendritic cell polarization. CatS is overexpressed in many solid cancers, and overall, it appears to promote an immune-suppressive and tumor-promoting microenvironment. While most data suggest that CatS inhibition or knockdown promotes anti-cancer immunity, cell-specific inhibition, especially in myeloid cells, appears to be important for therapeutic efficacy. This makes the design of CatS selective inhibitors and their targeting to tumor-associated M2-type macrophages (TAM) and DC an attr…
Targeting Neoepitopes to Treat Solid Malignancies: Immunosurgery
2020
Successful outcome of immune checkpoint blockade in patients with solid cancers is in part associated with a high tumor mutational burden (TMB) and the recognition of private neoantigens by T-cells. The quality and quantity of target recognition is determined by the repertoire of ‘neoepitope’-specific T-cell receptors (TCRs) in tumor-infiltrating lymphocytes (TIL), or peripheral T-cells. Interferon gamma (IFN-γ), produced by T-cells and other immune cells, is essential for controlling proliferation of transformed cells, induction of apoptosis and enhancing human leukocyte antigen (HLA) expression, thereby increasing immunogenicity of cancer cells. TCR αβ-dependent therapies should account f…
Exosome-mediated drug resistance in cancer: the near future is here.
2016
Drug resistance exerts a crucial role in several cancer treatments. Understanding the resistance mechanisms against different therapeutic agents can be helpful to determine the prognosis, but remains a tricky task. In this context, tumor-derived exosomes (TDEs) may give crucial answers about these resistance mechanisms. Exosomes are biological nanovesicles with an average size around 30–100 nm of diameter (Figure 1) that originate from the endocytic pathway by the inward budding of multivesicular bodies (MVB), and they function as cell-free messengers, involved in the cell–cell communication [Kowal et al. 2014]. It has been demonstrated that both cells in physiological and pathological cond…
AB052. P-20. Phase 2, open-label study of second-line M7824 treatment in patients with locally advanced or metastatic biliary tract cancer
2019
BACKGROUND: Transforming growth factor β (TGF-β) signaling promotes tumor immunosuppression; its inhibition in the tumor microenvironment may enhance the response to anti-PD-L1 treatment. M7824 is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 mAb against PD-L1. Building upon encouraging efficacy observed in a phase 1 study, the present study will evaluate M7824 clinical benefit in patients with pretreated biliary tract cancer (BTC). METHODS: This multicenter, international trial is evaluating M7824 monotherapy in patients with locally advanced or metastatic (LA/M) BTC unselected for tumor PD-L1…
Macrophage Factor Xa Signaling Promotes Cancer Immune Evasion
2018
Abstract Coagulation signaling through protease activated receptors (PARs) participates in inflammation and immunity. In cancer, tissue factor (TF) driven signaling via PAR2 promotes tumor progression, but effective pharmacological strategies to inhibit the PAR2 activating proteases for clinical anti-cancer benefit are currently unknown. To gain a better understanding of signaling by coagulation proteases, we generated PAR2 mouse strains with mutations that abolish canonical proteolysis by all proteases including FVIIa (PAR2 R38E) or create specific resistance to cleavage by the TF-FVIIa-Xa signaling complex (PAR2 G37I) that requires the endothelial cell protein C receptor (EPCR, Procr). As…
Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden
2018
Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast two-hybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2'…
Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1
2021
Abstract Richter’s transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase–associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurren…
Targeting myeloid cells in the tumor sustaining microenvironment.
2017
Myeloid cells are the most abundant cells in the tumor microenvironment (TME). The tumor recruits and modulates endogenous myeloid cells to tumor-associated macrophages (TAM), dendritic cells (DC), myeloid-derived suppressor cells (MDSC) and neutrophils (TAN), to sustain an immunosuppressive environment. Pathologically overexpressed mediators produced by cancer cells like granulocyte-macrophage colony-stimulating- and vascular endothelial growth factor induce myelopoiesis in the bone marrow. Excess of myeloid cells in the blood, periphery and tumor has been associated with tumor burden. In cancer, myeloid cells are kept at an immature state of differentiation to be diverted to an immunosupp…
Una visión integral del cáncer (II). Campos de estudio y biomarcadores emergentes
2019
Pathology and clinical oncology work hand in hand so that techniques and treatments, biomarkers and antibodies share the common goal of identifying integral new treatment regimens that are more effective and less aggressive. Evidence shows how tissue mechanics affect carcinogenesis and that tumor heterogeneity depends on metabolic stromal alteration and the Warburg effect of malignant cells, regulated directly by PD-1, becoming a target for immunotherapy. Proliferation and apoptosis depend on mitochondrial dysfunction in tumor cells, determining the grade of chemo/radio-resistance. The status of intestinal microbiota regulates immune response, tumor microenvironment structure and oncologic …
Les lymphocytes Th9
2016
Th9 cells are CD4 T helper cells characterized by their ability to produce IL-9 and IL-21. These cells are obtained from naive CD4(+) T cells cultured in the presence of TGF-β and IL-4. Thus their differentiation results from the balance between the signaling pathways induced by IL-4 in one hand and the one induced by TGF-β in the other hand. These cells are inflammatory cells and were first described in the context of atopic and autoimmune diseases in which they have a pathogenic role. They are also involved in the defense against parasite infections. Recently, some reports defined Th9 anticancer properties through their cytokine secretion. Indeed, their high secretion of IL-9 and IL-21 in…