Frontiers in immunology
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Frontiers in immunology · Jan 2019
ReviewCAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment.
Chimeric antigen receptor (CAR) T cells, T cells that have been genetically engineered to express a receptor that recognizes a specific antigen, have given rise to breakthroughs in treating hematological malignancies. However, their success in treating solid tumors has been limited. The unique challenges posed to CAR T cell therapy by solid tumors can be described in three steps: finding, entering, and surviving in the tumor. ⋯ Additionally, the immunosuppressive tumor microenvironment has implications for T cell function in terms of differentiation and exhaustion, and combining CARs with checkpoint blockade or depletion of other suppressive factors in the microenvironment has shown very promising results to mitigate the phenomenon of T cell exhaustion. Finally, identifying and overcoming mechanisms associated with dysfunction in CAR T cells is of vital importance to generating CAR T cells that can proliferate and successfully eliminate tumor cells. The structure and costimulatory domains chosen for the CAR may play an important role in the overall function of CAR T cells in the TME, and "armored" CARs that secrete cytokines and third- and fourth-generation CARs with multiple costimulatory domains offer ways to enhance CAR T cell function.
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Frontiers in immunology · Jan 2019
Discovery of Alpha-Gal-Containing Antigens in North American Tick Species Believed to Induce Red Meat Allergy.
Development of specific IgE antibodies to the oligosaccharide galactose-α-1, 3-galactose (α-gal) following tick bites has been shown to be the source of red meat allergy. In this study, we investigated the presence of α-gal in four tick species: the lone-star tick (Amblyomma americanum), the Gulf-Coast tick (Amblyomma maculatum), the American dog tick (Dermacentor variabilis), and the black-legged tick (Ixodes scapularis) by using a combination of immunoproteomic approach and, carbohydrate analysis. Anti-α-gal antibodies identified α-gal in the salivary glands of both Am. americanum and Ix. scapularis, while Am. maculatum and De. variabilis appeared to lack the carbohydrate. ⋯ Consistent with the glycan analysis, salivary samples from Am. americanum and Ix. scapularis stimulated activation of basophils primed with plasma from α-gal allergic subjects. Together, these data support the idea that bites from certain tick species may specifically create a risk for the development of α-gal-specific IgE and hypersensitivity reactions in humans. Alpha-Gal syndrome challenges the current food allergy paradigm and broadens opportunities for future research.
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Frontiers in immunology · Jan 2019
Neutrophil Effector Functions Are Not Impaired in Duffy Antigen Receptor for Chemokines (DARC)-Null Black South Africans.
Neutrophils are well-recognized for their pathogen killing mechanisms and disorders of neutrophil count and function are associated with recurrent infections. The Duffy Antigen Receptor for Chemokines (DARC)-null genotype is predominant in sub-Saharan African ancestry populations and is the major genetic determinant of benign ethnic neutropenia which has been associated with increased risk of Human Immunodeficiency Virus (HIV)-1 acquisition and mother-to-child transmission. However, the impact of DARC-null-linked neutropenia on HIV disease progression remains controversial. ⋯ ROS was unaffected by DARC trait irrespective of HIV status. Furthermore, formation of NETs was reduced in neutrophils from DARC-null subjects (p = 0.04) following prolonged in vitro stimulation, but only in HIV-1 infected subjects. The data indicate differential neutrophil function in the absence of DARC that may be moderately modulated by HIV-1 infection but overall, the data suggest that DARC-null trait is not deleterious to neutrophil effector functions in African populations.
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Frontiers in immunology · Jan 2019
ReviewIs There a Place for Immunotherapy for Metastatic Microsatellite Stable Colorectal Cancer?
Immunotherapy using checkpoint inhibitor targeting PD-1 and PD-L1 revolutionized the treatment of microsatellite instable metastatic colon cancer. Such treatment is now a standard of care for these patients. ⋯ Recent advances in biology provide a rationale for this intrinsic resistance and support the evaluation of combination therapy to reverse resistance. This article will highlight recent findings on the mechanism of intrinsic resistance and recent advances in clinical trials for combination therapy.
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Frontiers in immunology · Jan 2019
Polarization of Human Monocyte-Derived Cells With Vitamin D Promotes Control of Mycobacterium tuberculosis Infection.
Background: Understanding macrophage behavior is key to decipher Mycobacterium tuberculosis (Mtb) pathogenesis. We studied the phenotype and ability of human monocyte-derived cells polarized with active vitamin D [1,25(OH)2D3] to control intracellular Mtb infection compared with polarization of conventional subsets, classical M1 or alternative M2. Methods: Human blood-derived monocytes were treated with active vitamin D or different cytokines to obtain 1,25(OH)2D3-polarized as well as M1- and M2-like cells or fully polarized M1 and M2 subsets. ⋯ This ability was associated with high mRNA levels of pro-inflammatory cytokines and the antimicrobial peptide LL-37 but also anti-inflammatory IL-10, while expression of the immunosuppressive enzyme IDO (indoleamine 2,3-dioxygenase) remained low in Mtb-infected 1,25(OH)2D3-polarized cells compared with the other subsets. Conclusions: Mtb infection promoted a mixed M1/M2 macrophage activation, and 1,25(OH)2D3-polarized monocyte-derived cells expressing LL-37 but not IDO, were most effective to control intracellular Mtb growth. Macrophage polarization in the presence of vitamin D may provide the capacity to mount an antimicrobial response against Mtb and simultaneously prevent expression of inhibitory molecules that could accelerate local immunosuppression in the microenvironment of infected tissue.