No abstract

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths. Among breast cancers (BC) subtypes, triple-negative (TN) BC, is characterized by metastatic progression and poor patient prognosis. Although, TNBC is initially sensitive to chemotherapy, many TNBC patients rapidly develop resistance, at which point metastatic disease is highly lethal. Cancer cells present phenotypic changes or molecular signatures that distinguish them from healthy cells. The Tn antigen (GalNAc-O-Thr/Ser), that constitutes a powerful tool as tumour marker, was recently reported to contribute to tumour growth. However, its role in BC-derived metastasis has not yet been addressed. In this work we generated a pre-clinical orthotopic Tn+ model of metastatic TNBC, that mimics the patient surgical treatment and is useful to study the role of Tn in metastasis and immunoregulation. We obtained two different cell clones which differed in their Tn antigen expression: a high Tn-expressing and a non-expressing clone. Interestingly, the Tn-positive cell line generated significantly larger tumours and higher degree of lung metastases associated with a lower survival rate than the Tn-negative and parental cell line. Furthermore, we also found that both tumours and draining-lymph nodes from Tn+-tumour bearing mice presented a higher frequency of CD4+ FoxP3+ T cells, while their splenocytes expressed higher levels of IL-10. In conclusion, this work suggests that the Tn antigen participates in breast tumour growth and spreading, favouring metastases to the lungs that are associated to an immunoregulatory state, suggesting that Tn-based immunotherapy could be a strategy of choice to treat these tumours.

No abstract

Gastrointestinal nematode infections, including Haemonchus contortus, are one of the main causes of economic losses to ovine farmers worldwide. In order to contribute to the control of nematode infections and avoid parasite spreading we generated divergent resistant and susceptible sheep breeds and evaluated the adaptive immunity of these animals developed upon experimental infection against H. contortus. The selection of resistant or susceptible animals from the Corriedale Breed has been based on Expected Progeny Differences for faecal egg counts per gram. Furthermore, animals from the resistant Corriedale line were inseminated with imported semen from Australian Rylington Merino rams. Thus, the objective of this work was to analyze the adaptive immune response in both susceptible and resistant obtained lambs. Our results indicate that there is a potent parasite-specific local and systemic immune response in resistant animals and that although susceptible lambs can produce high levels of IgA antibodies during the infection, their antibody response is delayed which, together with an impaired specific-Th2 response, does not contribute to initial parasite elimination. Our results shed light into the immune mechanisms that mediate resistance to H. contortus and could constitute important assets to sheep farmers, not only as a means to detect resistance, but also to enhance the efficiency of selection in stud flocks.

Fasciola hepatica is a fluke that infects livestock and humans causing fasciolosis, a zoonotic disease of increasing importance due to its worldwide distribution and high economic losses. The parasite regulates the host immune system by inducing a strong Th2 and regulatory T (Treg) cell immune response through mechanisms that might involve the expression or activity of heme-oxygenase-1 (HO-1), the rate-limiting enzyme in the catabolism of free heme that also has immunoregulatory and antioxidant properties. In this paper, we show that F. hepatica-infected mice upregulate HO-1 on peritoneal antigen-presenting cells (APC), which produce decreased levels of both reactive oxygen and nitrogen species (ROS/RNS). The presence of these cells was associated with increased levels of regulatory T cells (Tregs). Blocking the IL-10 receptor (IL-10R) during parasite infection demonstrated that the presence of splenic Tregs and peritoneal APC expressing HO-1 were both dependent on IL-10 activity. Furthermore, IL-10R neutralization as well as pharmacological treatment with the HO-1 inhibitor SnPP protected mice from parasite infection and allowed peritoneal APC to produce significantly higher ROS/RNS levels than those detected in cells from infected control mice. Finally, parasite infection carried out in gp91phox knockout mice with inactive NADPH oxidase was associated with decreased levels of peritoneal HO-1+ cells and splenic Tregs, and partially protected mice from the hepatic damage induced by the parasite, revealing the complexity of the molecular mechanisms involving ROS production that participate in the complex pathology induced by this helminth. Altogether, these results contribute to the elucidation of the immunoregulatory and antioxidant role of HO-1 induced by F. hepatica in the host, providing alternative checkpoints that might control fasciolosis.