Low-dose neoadjuvant chemotherapy dominates Ki67− quiescent tumor dormancy for an effective immunotherapy of breast cancer

Abstract

Abstract Breast cancer mortality is mainly due to distant recurrence of the disease. The disease recurrence is usually because of the establishment of tumor dormancy following successful treatment of early stage breast cancer. In current clinical practice, dormant tumor cells are not actively treated, because they do not respond to chemotherapy or radiation therapies. Immunotherapeutic targeting of tumor dormancy is also challenging because of the induction of tumor immunoediting, leading to tumor escape and relapse. Recently, we have characterized Ki67− quiescent and Ki67low indolent types of tumor dormancy. We demonstrated that quiescent, but not indolent, dormant tumor cells fail to undergo immunoediting and remain highly susceptible to immunotherapy. Here, we sought to develop neoadjuvant therapies for dominating a quiescent type of tumor dormancy as the best target for immunotherapy. We showed that a low dose 5-FU+Adriamycin+Cyclophosphamide (FAC) dominated Ki67− quiescent type of tumor dormancy in the neu-overexpression mouse mammary carcinoma (MMC) tumor cells. These dormant cells were effectively controlled by immunotherapy in FVBN202 transgenic mouse model of spontaneous breast cancer. Since the antibiotic azithromycin has been shown to effectively eliminate senescent cells, we also sought to determine its efficacy against dormant tumor cells. We demonstrated that azithromycin specifically induced apoptosis in FAC-induced dormant tumor cells. All together, the results suggest that use of less toxic, low dose chemotherapy combined with azithromycin in a neoadjuvant setting could lead to the elimination of dormant tumor cells by immunotherapy.