This study aimed to assess the effects of three doxorubicin, paclitaxel or carboplatin-containing neoadjuvant chemotherapy regimens on tumor infiltrating lymphocytes and immune checkpoints in a murine model of triple-negative breast cancer (BC).
Syngeneic model of locally-advanced BC was established in immunocompetent mice using 4T1 cell line. Tumor-bearing animals were treated with human-equivalent dosages of doxorubicin, paclitaxel, paclitaxel and carboplatin combination (PCb), and placebo. Infiltration of CD3+, CD8+, and FoxP3+ cells into the tumor were assessed by immunohistochemistry. Expression of immune checkpoints including PD-1, CTLA-4, and TIM-3 were assessed by real-time PCR.
In our study, absolute count of CD3+ and CD8+ cells was significantly (p < 0.0001) higher in tumors treated with doxorubicin when compared to the other groups. The relative expression of PD-1 was significantly (p < 0.05) lower in tumors treated with doxorubicin when compared to tumors of the control group. PCb regimen decreased the expression of PD-1 in tumor tissues significantly (p < 0.05) compared to the placebo. Tumors treated with doxorubicin presented significantly (p < 0.05) lower expressions of TIM-3 when compared to the other groups.
Our results suggest that neoadjuvant chemotherapy of triple-negative BC with doxorubicin enhances anti-tumor immunity via increased infiltration of TILs. It also seems that doxorubicin inhibits immunosuppression in tumor by down-regulation of PD-1 and TIM-3 immune checkpoints. The study data demonstrate that PCb regimen can also decrease expression of PD-1. The data also raise new questions about the efficacy of PD-1 inhibitors after neoadjuvant chemotherapy with doxorubicin or PCb.
Deputy of Research - Tehran University of Medical Sciences.
Tehran University of Medical Sciences.
All authors have declared no conflicts of interest.