The BC has surpassed lung cancer to be the most commonly diagnosed cancer in people worldwide. Chemotherapy has been used to treat cancer for over 70 years. Although it started later than radiotherapy, chemotherapy is like a spark in BC treatment. Neoadjuvant chemotherapy allows distant metastases of tumors to be treated earlier and more effectively, which demonstrated that it could downstage the primary lesions and regional lymph nodes of BC so that the previously inoperable tumors can be performed radical surgery after the downstage and may improve the long-term survival rate of BC patients, especially the survival rate of patients who achieve complete remission after chemotherapy can be significantly improved. Moreover, it can provide valuable information about the chemotherapeutic sensitivity of tumors in vivo, subsequently providing a basis for selecting postoperative adjuvant chemotherapy regimens. Additionally, neoadjuvant chemotherapy can enable cytotoxic drugs to reach the tumor's interior through the intact tumor blood vessels and avoid reducing the chemotherapy drug concentration in tumor tissues due to changes in the tumor vascular bed after surgery. Consequently, this approach enhances the efficacy of chemotherapy. Consistent with the findings of recent studies, our data showed three cases of metastases where the response to chemotherapy was either PD or SD, indicating that the effect of chemotherapy could predict the clinical prognosis. The fact that 20–30% of patients would not benefit from neoadjuvant chemotherapy prompted us to investigate a biomarker that could predict the effectiveness of this treatment.
The Th-17 is one of the lineages of CD4+ T cells for producing IL-17a, which acts as a heterodimeric form with IL-17F [19, 20]. In BC, IL-17a was reported to promote BC proliferation by MAPK (P38, JNK, and ERK1/2) and NK-κB [21–24]. Additionally, IL-17a promotes the expression of TGF-β, TNF-α, IL-6, IL-8, and IL-1β, which is essential in promoting tumor growth, angiogenesis, invasion, and metastasis [25]. Moreover, IL-17a is reported to be involved in tumor cell invasion and metastasis through the MMP pathway. The MMP-9 inhibitors could decrease BC cell invasion in mouse models [26]. Furthermore, the IL-17a pathway activated NK-κB to promote bone metastasis. Subsequently, NF-κB-related expression of MMP-2 and MMP-9 are an important driving force in the invasiveness and metastasis of various human cancers, including colorectal cancer, hepatocellular cancer, nasopharyngeal carcinoma, and non-small cell lung cancer [27–30]. These reports are potential evidence that IL-17a may act as a prognostic indicator of BC. Although our results did not prove that IL-17a was correlated with prognosis, there is a trend that higher IL-17a level is correlated with poorer prognosis, which may be due to insufficient sample size. However, elevated IL-17a expression is strongly associated with poor prognosis outcomes for BC patients, which immunohistochemistry can still prove [31].
Interestingly, our data proved that IL-17a was a predictor for chemotherapy and was downregulated by chemotherapy. A previous study has shown that IL-17a can promote docetaxel chemoresistance through ERK1/2 pathway and EGFR phosphorylation [32]. However, the specific mechanism by which chemotherapy leads to IL-17a downregulation remains unclear. IL-17a has been demonstrated to promote angiogenesis by promoting vascular endothelial growth factor (VEGF) secretion by tumor cells [33]. This suggests that promoting angiogenesis by IL-17a can improve the accessibility of chemotherapy drugs to tumors. Overall, IL-17a directly promotes tumor growth, invasion, and metastasis. Additionally, there is more evidence that IL-17a negatively regulates the immune response in cancer patients by recruiting myeloid suppressor cells (MDSCs) [34]. Moreover, an increase in IL-17a is associated with neutrophil-to-lymphocyte ratio (NLR) and stimulation of programmed death ligand 1 (PD-1), which are positively related to immune escape [35]. However, the potential biomarker of neoadjuvant therapy for BC is still controversial. Our data revealed important evidence that IL-17a expression level significantly predicts neoadjuvant chemotherapy sensitivity. All studies mentioned above can be used to demonstrate that higher IL-17a expression is related to poor responses in both pre- and post-treatment.
Briefly, we have indicated the important role of IL-17a in the context of neoadjuvant therapy. Specifically, we have emphasized that neoadjuvant therapy can down-regulate IL-17a expression, significantly predicting neoadjuvant chemotherapy sensitivity. Moreover, reduced IL-17a expression of baseline or after-treatment was significantly related to early stage, less lymphatic metastasis, and lower expression of ki67. However, IL-17a could not predict the PFS; after-treatment plasma IL-17a and its decreased degree were linked to the prognosis of patients undergoing neoadjuvant chemotherapy.
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