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- Joseph, A, et al.
(författare)
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Metabolic features of cancer cells impact immunosurveillance
- 2021
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types.MethodsTumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PARlow) and cisplatin-resistant (PARhigh) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry.ResultsThe infiltration of tumors by CD8 T and DC-LAMP+ cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=−0.39, p=0.034 in LACC, R=−0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PARhigh). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086).ConclusionsOncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.
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- Wang, GY, et al.
(författare)
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Immunostimulatory sequence CpG elicits Th1-type immune responses in inflammatory skin lesions in an atopic dermatitis murine model
- 2008
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Ingår i: International archives of allergy and immunology. - : S. Karger AG. - 1423-0097 .- 1018-2438. ; 147:1, s. 41-51
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background:</i> Atopic dermatitis (AD) is a chronic inflammatory skin disease, for which no fundamental therapy exists. Immunostimulatory sequence CpG (ISS CpG) has potential in reducing susceptibility to allergic diseases and reversing established allergic reactions. <i>Objective:</i> To investigate the effects of ISS CpG in the prevention and treatment of AD in an AD murine model. <i>Methods:</i> BALB/c mice were epicutaneously exposed to ovalbumin (OVA) for 3 or 4 weeks with a 2-week resting period between each exposure week. ISS i.d. injection was given either on the 1st day of each exposure week (in the prevention experiment) or 3 days before and on the 1st, 4th and 7th day of the last exposure week (in the treatment experiment). Skin biopsy and blood were obtained at the end of the experiments. <i>Results:</i> ISS CpG treatment increased drastically mRNA expression of proinflammatory and Th1-type cytokines and chemokines in OVA-treated skin both in the prevention and treatment experiments. The suppressing effect of ISS CpG on Th2-type cytokines and chemokines was weak and limited to IL-13 and CCL24 in the treatment experiment. No significant reduction in OVA-elicited infiltration of eosinophils and T cells in the skin was seen after ISS administration but infiltration of plasmacytoid dendritic cells was absent in ISS CpG-treated skin. In contrast, ISS injection elicited dramatic infiltration of F4/80+ and CCR5+ cells into the dermis and subcutaneous tissue. <i>Conclusion:</i> Due to unwanted side effects and minor beneficial effects in our model, administration of ISS CpG may not be suitable for the treatment of AD in humans.
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