Immunology
An engineered antibody fragment targeting mutant β-catenin via major histocompatibility complex I neoantigen presentation
Mutations in CTNNB1, the gene encoding β-catenin, are common in colon and liver cancers, the most frequent mutation affecting Ser-45 in β-catenin. Peptides derived from WT β-catenin have previously been shown to be presented on the cell surface as part of major histocompatibility complex (MHC) class I, suggesting an opportunity for targeting this common driver gene mutation with antibody-based therapies. Here, crystal structures of both the WT and S45F mutant peptide bound to HLA-A*03:01 at 2.20 and 2.45 Å resolutions, respectively, confirmed the accessibility of the phenylalanine residue for antibody recognition.A selective small-molecule inhibitor of macrophage migration inhibitory factor-2 (MIF-2), a MIF cytokine superfamily member, inhibits MIF-2 biological activity
Cytokine macrophage migration inhibitory factor-2 (MIF-2 or D-dopachrome tautomerase) is a recently characterized second member of the MIF cytokine superfamily in mammalian genomes. MIF-2 shares pro-inflammatory and tumorigenic properties with the clinical target MIF (MIF-1), but the precise contribution of MIF-2 to immune physiology or pathology is unclear. Like MIF-1, MIF-2 has intrinsic keto-enol tautomerase activity and mediates biological functions by engaging the cognate, common MIF family receptor CD74.Deimmunizing substitutions in Pseudomonas exotoxin domain III perturb antigen processing without eliminating T-cell epitopes
Effective adaptive immune responses depend on activation of CD4+ T cells via the presentation of antigen peptides in the context of major histocompatibility complex (MHC) class II. The structure of an antigen strongly influences its processing within the endolysosome and potentially controls the identity of peptides that are presented to T cells. A recombinant immunotoxin, comprising exotoxin A domain III (PE-III) from Pseudomonas aeruginosa and a cancer-specific antibody fragment, has been developed to manage cancer, but its effectiveness is limited by the induction of neutralizing antibodies.Natural killer cells induce distinct modes of cancer cell death: Discrimination, quantification, and modulation of apoptosis, necrosis, and mixed forms
Immune therapy of cancer is among the most promising recent advances in medicine. Whether the immune system can keep cancer in check depends on, among other factors, the efficiency of immune cells to recognize and eliminate cancer cells. We describe a time-resolved single-cell assay that reports the quality, quantity, and kinetics of target cell death induced by single primary human natural killer (NK) cells. The assay reveals that single NK cells induce cancer cell death by apoptosis and necrosis but also by mixed forms.Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells
CD4+ T helper 9 (Th9) cells are a newly discovered Th cell subset that produce the pleiotropic cytokine IL-9. Th9 cells can protect against tumors and provide resistance against helminth infections. Given their pivotal role in the adaptive immune system, understanding Th9 cell development and the regulation of IL-9 production could open novel immunotherapeutic opportunities. The Na+/H+ exchanger 1 (NHE1; gene name Slc9α1)) is critically important for regulating intracellular pH (pHi), cell volume, migration, and cell survival.Targeted Reconstitution of Cytokine Activity upon Antigen Binding using Split Cytokine Antibody Fusion Proteins
The targeted assembly of antibody products upon antigen binding represents a novel strategy for the reconstitution of potent therapeutic activity at the site of disease, sparing healthy tissues. We demonstrate that interleukin-12, a heterodimeric pro-inflammatory cytokine consisting of the disulfide-linked p40 and p35 subunits, can be reconstituted by sequential reassembly of fusion proteins based on antibody fragments and interleukin-12 subunit mutants. Analysis of the immunostimulatory properties of interleukin-12 and its derivatives surprisingly revealed that the mutated p35 subunit partially retained the activity of the parental cytokine, whereas the p40 subunit alone was not able to stimulate T cells or natural killer cells.Complement Membrane Attack and Tumorigenesis: A SYSTEMS BIOLOGY APPROACH
Tumor development driven by inflammation is now an established phenomenon, but the role that complement plays remains uncertain. Recent evidence has suggested that various components of the complement (C) cascade may influence tumor development in disparate ways; however, little attention has been paid to that of the membrane attack complex (MAC). This is despite abundant evidence documenting the effects of this complex on cell behavior, including cell activation, protection from/induction of apoptosis, release of inflammatory cytokines, growth factors, and ECM components and regulators, and the triggering of the NLRP3 inflammasome.A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen
Human CD8+ cytotoxic T lymphocytes can mediate tumor regression in melanoma through the specific recognition of HLA-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCRs), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumor immunity capable of breaking tolerance toward these self-antigens. However, previous studies have shown that these immunogenic designer peptides are not always effective.Novel Roles of c-Met in the Survival of Renal Cancer Cells through the Regulation of HO-1 and PD-L1 Expression
Background: Tyrosine kinase receptor c-Met plays critical roles in the growth of RCC.Results: c-Met-mediated Ras activation and HO-1 overexpression promote anti-apoptotic signals, and increase PD-L1 expression, which inhibits immune cell-mediated killing of RCC cells.Conclusion: c-Met-induced HO-1 and PD-L1 expression promotes RCC cell survival.Significance: HO-1 and PD-L1 can serve as novel therapeutic targets for c-Met-induced RCC.
