Direct Synergistic Effect of Immunotherapy and Chemotherapy as a New Paradigm in Treatment of Breast Cancer

摘要

Treatment of patients with advanced stages of breast cancer remains an unresolved clinical problem. The main objectives of this study are to determine whether immunotherapy sensitizes tumor to chemotherapy and to identify some of the main mechanisms of this effect. We investigated the possibility of a direct synergy between immunotherapy and chemotherapy in vitro. We found that pre-treatment of tumor target cells with doxorubicin or paclitaxel significantly increased cytotoxic effect of T-lymphocytes. Importantly, that effect was antigen-specific, since it was observed only in tumor cells loaded with specific but not a control peptide. In contrast, pre- treatment of splenocytes did not result in enhancement of target cell killing. In parallel experiments we have determined that both drugs increased the expression of p53 in tumor cells. However, that increase observed only after 48 hr of treatment and therefore could not contribute to observed sensitization of tumor cells to CTLs. To determine the effect of the combined treatment in vivo, mammary carcinoma TUBO was established s.c. in BALB/c mice. Dendritic cell vaccine alone slowed down tumor growth, which was consistent with previous results obtained by many laboratories. Paclitaxel had similar effect. However, in both cases tumor growth resumed in about a week after end of the treatment. In a sharp contrast, tumor size was substantially reduced in mice treated with combination of DC vaccine and chemotherapy. We have identified the mechanism of this phenomenon. We have found that chemotherapy make tumor cells permeable to granzime B released by CTLs. This effect was perforin in dependent and was mediated by mannose-6-phosphate receptor up-regulated on the surface of tumor cells by chemotherapy. Thus, this data indicates that a direct combination of chemotherapy with cancer vaccine provides substantial antitum.