Xeroderma Pigmentosum (XP), an autosomal recessive disorder characterized by ultraviolet radiation-induced abnormalities of
DNA excision and repair pathways is associated with early development of cutaneous
cancers. Intracellular oxidative stress has also been proposed as a contributor to the occurrence of
skin cancers. However, little is known about the possible augmentative contributions of chronic
inflammation, immune suppression and oxidative stress to the pathogenesis of
malignancies associated with other subtypes of XP. This has been addressed in the current study, focused on the measurement of systemic
biomarkers of
inflammation, immune dysfunction and oxidative damage in XP patients, consisting of XP-C, XP-D and XP-E cases, including those XP-C cases who had already developed multiple skin
malignancies. The inflammatory
biomarker profile measured in XP patients and healthy control subjects included the
cytokines,
interleukins (ILs)-2, -4, -6, -10,
interferon-γ (IFN- γ) and
tumor-necrosis factor-α (TNF-α), the
acute phase reactant,
C-reactive protein (CRP), and
cotinine (as an objective
indicator of smoking status). Immune suppression was detected according to the levels of five soluble inhibitory
immune checkpoint proteins (CTLA-4, PD-1, PD-L1, LAG-3 and TIM-3), as well as those of
vitamin D, while oxidative stress was determined according to the circulating levels of the
DNA adduct, 8-hydroxy-2-deoxyguanosine (8-OH-dG). These various
biomarkers were measured in plasma using immunofluorimetric, nephelometric and ELISA procedures. Significant elevations in
IL-6 (P<0.01) and TNF-α (P<0.0001), but none of the other
cytokines, as well as increased levels of all five soluble inhibitory immune checkpoints (P=0.032-P=0.0001) were detected in the plasma of the XP patients.
C-reactive protein and
vitamin D were increased and decreased, respectively (both P<0.0001), while only one participant had an elevated level of plasma
cotinine. Surprisingly, the levels of
8-OH-dG were significantly (P=0.0001) lower in the group of XP patients relative to a group of healthy control subjects. The findings of increased levels of pro-inflammatory
cytokines and, in particular, those of the soluble immune checkpoints, in the setting of decreased
vitamin D and moderately elevated levels of CRP in XP patients suggest a possible secondary role of ongoing, inflammatory stress and immune suppression in the pathogenesis of XP-associated
malignancies.