Triple-negative breast cancer (TNBC) has the worst outcome among all breast cancer subtypes because of its high rate of metastatic spread and recurrence. Standard first-line treatment for TNBC is chemotherapy (chemo) combinations. However, many (~50%) TNBC patients do not respond well to chemo-treatment, and new treatment options are needed. Immune checkpoint blockade (ICB) has led to a breakthrough in treating various types of cancers with durable responses in advanced cancer. However, its efficacy for treating TNBC is unsatisfactory, partly because breast cancers are not highly immunogenic. Additionally, the efficacy of ICB for inhibition of distant metastases has not been systematically examined. Here, we tested whether using an immunogenic chemotherapy - Doxorubicin or Doxisome (liposomal encapsulated formulation of Doxorubicin) may enhance the efficacy of anti-PD1 antibody (an ICB regimen), in the 4T1-TNBC mouse model, which is highly resistant to ICB. Also, we used the spontaneous metastatic models of TNBC in mice to test the therapeutic efficacy of neoadjuvant immunogenic chemo plus ICB in inhibition of metastasis after primary mammary tumor resection. Indeed, the combination of a low dosage of Doxo or Doxisome with anti-PD-1 antibody inhibited mammary tumor growth and improved the survival of mice bearing 4T1 mammary tumor significantly (P<0.05) better than Doxo or Doxisome or anti-PD-1 antibody alone. The antitumor response was triggered by direct immunogenic chemo drug actions on tumor cells, which induced infiltration of antigen presenting cells (e.g. DCs), and ultimately CD8+ T cell antitumor immunity. More strikingly, we found that neoadjuvant chemo plus ICB eliminated lung metastases following primary tumor resection significantly (P<0.05) more effective than single treatment with chemo or ICB. Flow cytometry analyses revealed highly significantly (P<0.05) increased antigen-specific T cells infiltration in lung metastases of mice who received the combination (Chemo plus ICB) treatment. These data provide a strong scientific rationale for several ongoing clinical trials combining immunogenic chemotherapy with anti-PD-1 checkpoint blockade therapy, which could be highly effective in treating metastatic breast cancer. The efficacy of combining immunogenic chemotherapy with anti-PD-1 checkpoint blockade therapy in inhibition of others ICB resistant solid tumors and metastasis should be further investigated.
Citation Format: Xiangliang Yuan, Yi Xiao, Xianghua Liu, Wenling Kuo, Hongzhong Li, Ping Li, Hideo Yagita, Dihua Yu. Effective inhibition of metastasis in triple-negative breast cancer (TNBC) mouse model by combining immunogenic chemotherapy and immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4565.