Clearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-g and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-g 2/2 mice succumb rapidly to STm infections, T-bet 2/2 mice do not. In this study, we assess the anatomy of immune responses and the relationship with bacterial localization in the spleens and livers of STminfected IFN-g 2/2 and T-bet 2/2 mice. In IFN-g 2/2 mice, there is deficient granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination of bacteria throughout the organs, and rapid death. The provision of a source of IFN-g reverses this, coincident with subsequent granuloma formation and substantially extends survival when compared with mice deficient in all sources of IFN-g. T-bet 2/2 mice induce significant levels of IFN-g 2 after challenge. Moreover, T-bet 2/2 mice have augmented IL-17 and neutrophil numbers, and neutralizing IL-17 reduces the neutrophilia but does not affect numbers of bacteria detected. Surprisingly, T-bet 2/2 mice exhibit surprisingly wild-type-like immune cell organization postinfection, including extensive iNOS + granuloma formation. In wild-type mice, most bacteria are within iNOS + granulomas, but in T-bet 2/2 mice, most bacteria are outside these sites. Therefore, Th1 cells act to restrict bacteria within IFN-g-dependent iNOS + granulomas and prevent dissemination.
B cell precursor acute lymphoblastic leukemia (BCP-ALL) is a malignant disorder of immature B lineage immune progenitors and is the commonest cancer in children. Despite treatment advances it remains a leading cause of death in childhood and response rates in adults remain poor. A preleukemic state predisposing children to BCP-ALL frequently arises in utero, with an incidence far higher than that of transformed leukemia, offering the potential for early intervention to prevent disease. Understanding the natural history of this disease requires an appreciation of how cell-extrinsic pressures, including microenvironment, immune surveillance and chemotherapy direct cell-intrinsic genetic and epigenetic evolution. In this review, we outline how microenvironmental factors interact with BCP-ALL at different stages of tumorigenesis and highlight emerging therapeutic avenues.
Leucine-rich repeat-containing G-protein receptor 5 (LGR5) has been characterised as a stem cell and cancer stem cell marker. Previous analyses of LGR5 transcript levels indicate high level expression discriminates malignancies such as colorectal cancer (CRC) and pre-B acute lymphoblastic leukaemia (pre-B ALL) from healthy tissues suggesting LGR5 protein expression may provide a molecular handle for prognosis and treatment. We have developed highly specific, high affinity antibodies to the extracellular domain of human LGR5 (a-LGR5) that detect high LGR5 protein levels in colorectal cancer (CRC), hepatocellular carcinoma (HCC), and pre-B ALL. In contrast, there is low to undetectable levels of LGR5 protein in normal colon and rectal epithelia, liver, ovarian tissues, brain and immune cell types. LGR5 is rapidly internalised from the plasma membrane and trafficked to intracellular vesicular compartments including lysosomes. Treatment of high LGR5-expressing CRC and pre-B ALL cancer cell lines with an antibody-drug conjugate version of a-LGR5 (a-LGR5-ADC) lead to effective cell killing at nanomolar concentrations. Interventional treatment of pre-B ALL tumours with a-LGR5-ADC in vivo led to rapid tumour attrition. We further demonstrated the therapeutic utility of humanised a-LGR5 by using the corresponding scFv fragment for the generation of a-LGR5 chimeric antigen receptors (CARs) and a Bispecific T cell Engager (BiTE). a-LGR5-CAR-NK cells were effective at killing LGR5-expressing cells while a-LGR5/a-CD3 BiTEs induce T cell activation and killing of NALM6 cells by cytotoxic CD8+ T cells. Taken together, this study establishes a-LGR5-based therapeutic modalities that effectively discriminate and target CRC, HCC and pre-B ALL tumour cells.
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