177P - The Immune-microenvironment Confers Chemoresistance in Breast cancer through activation of VEGFR2/STAT3/BIRC5 signaling

Background

Chemotherapy with Taxanes is often the preferred clinical treatment for breast cancer patients. Unfortunately, these agents become increasingly ineffective during treatment. Pro-tumoral M2 tumor-associated macrophages (TAMs) are the most abundant immune cells in the breast tumor microenvironment. In a first-in-human study (NCT00358163, NCT00731861), Vatalanib (PTK787/ZK) was well tolerated alone or in combination with paclitaxel. Here, we explored the pre-clinical efficacy of combination of Vatalanib and paclitaxel in TAM-induced chemoresistance in breast cancer.

Methods

We reported translational analysis of expression of BIRC5 and its correlation with Overall Survival (OS) in breast cancer patients. Western blotting, immunofluorescence imaging, and Real-time PCR analysis were used to determine survivin (BIRC5), pVEGFR2 and STAT3 in vitro. 4T1 cells and RAW 264.7 cells were injected in BALB/c mice to generate syngeneic chemoresistant breast tumor model in vivo.

Results

We measured survivin (BIRC5) upregulation in breast tumor (n=288) as compared to normal breast tissue (n=211) using TCGA datasets. Further, retrospective study confirmed that an increase in BIRC5 expression decreases Overall Survival (OS) in breast cancer. Using the invitro co-culture system, we validated that the macrophage secreted VEGF-A contributes to chemoresistance against paclitaxel. Mechanistically, VEGFA, by binding to VEGFR2, activated the transcription factor STAT3 leading to increased expression of anti-apoptotic protein survivin in breast cancer cells. Therapeutically, the TAM-induced STAT3/survivin signaling could be abrogated by Vatalanib thereby reversing the chemoresistance. The data shows that the combination of paclitaxel with Vatalanib exhibit reduced M2-TAMs, indicating that the combination effectively altered tumor microenvironment in the in vivo 4T1 breast tumor model.

Conclusions

Together, our study revealed the role of TAMs in conferring paclitaxel resistance in breast cancer. Combinatorial VEGFR2 blockade and paclitaxel chemotherapy decreased TAM population and showed better prognostic outcomes in breast cancer.

Legal entity responsible for the study

B. Deswal, S. Kapoor.

Funding

Department of Biotechnology, Government of India; Department of Science and Technology, Government of India.

Disclosure

All authors have declared no conflicts of interest.