الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Breast cancer is still the malignancy with the highest prevalence worldwide. In Egypt, BC has become the most prevalent cancer, surpassing liver cancer. Similar to other cancers, inflammation may exhibit both pro- and anti-tumor features in the context of BC. While acute inflammation in early breast carcinogenesis is beneficial for stimulation of anti-tumor immune responses, chronic inflammation, by contrast, is a major contributor to BC initiation and development. One of the key components of these inflammatory milieus are cytokines.
Overall, IL-12 is an effector pro-inflammatory cytokine that has been shown to engage anti-tumor immunity. On the other hand, IL-35 is a strong anti-inflammatory cytokine that primarily promotes immunosuppression and tumorigenesis. Consequently, the former is a potent immunomodulatory factor for cancer treatment, while the latter is a potential target for antitumor therapy.
Harnessing inflammation with TLR agonists is becoming one of the arsenals of cancer immunotherapy. To this end, TLR agonists are currently being investigated, alone or in combination, to promote beneficial acute inflammatory responses. One of these TLR agonists is RSQ, a TLR7/8 agonist that has exhibited a robust antitumor effect in several tumors models, including BC. However, the precise influence of RSQ on the balance between pro- and anti-inflammatory cytokines in BC patients is still poorly understood. Hence, we set out to assess the effect of RSQ on the balance between IL-12 and IL-35 as pro- and anti-inflammatory cytokines, respectively, in BC patients.
For this purpose, we recruited 26 female patients with invasive non-metastatic BC who did not have surgery or receive neoadjuvant therapy, along with 20 healthy, age-matched females as a control group. Peripheral venous blood was withdrawn from enrolled participants to isolate PBMCs which were then cultured and stimulated with RSQ. Unstimulated cultured cells were included as negative controls. IL-12 and IL-35 were finally quantified in culture supernatants using commercial human IL-12p70 and IL-35 sandwich ELISA kits.
Our results showed that baseline IL-12 levels were slightly lower in BC patients compared to healthy controls, but not statistically significant. Conversely, IL-35 levels were significantly higher in BC patients. Accordingly, the IL-12/IL-35 ratio was significantly lower in BC patients. In other words, the significantly high IL-35 level was the chief contributor to the bias towards the anti-inflammatory side in BC patients.
Stimulation of PBMCs with RSQ significantly increased IL-12 levels in both groups, with no statistically significant difference between them. Contrarily, IL-35 levels decreased significantly in both groups but were more significantly lowered in control group. Resiquimod significantly raised the IL-12/IL-35 ratio in both groups but more significantly in the control group. Generally, the significant increase observed in the IL-12/IL-35 ratio was attributed to the significant reduction in IL-35.
Regarding subgroup analysis, except for LI and LVI, no significant associations were found between clinicopathological features of BC patients and cytokine ratios after RSQ stimulation. IL-12/IL-35 ratios in both, LI and LVI negative BC patients, were markedly higher than their positive counterparts.