Analysis of cytotoxic T lymphocytes response activated dendritic cells vaccination using breast cancer stem-like cells

Abstract

Breast cancers have high recurrence rates with current treatment remaining palliative. Especially breast cancer–initiating cells have been recently identified in breast carcinoma as CD44⁺/CD24^-/low cells, which exclusively retain tumorigenic activity and display stem cell–like properties. Immunotherapies harness the body’s own immune system to target cancers and could overcome the limitations of conventional treatments. One active immunotherapy strategy uses dendritic cell (DC)-based vaccination to initiate T-cell-mediated antitumor immunity. However, whether using human BSC antigens may improve the antitumor effect of DC vaccination against BSC is indistinct. In this study, we isolated and evaluated BSCs derived from breast cancer patients, and explored the suitability of BSCs as sources of antigens for DC vaccination again human BSCs, with the aim of achieving BSC targeting and enhanced antitumor immunity. We found that BSCs express high levels of stem cell-associated molecules, CD44⁺/CD24^- and CD133⁺, but adherent cells express CD44⁺/CD24⁺ and low CD133⁺. The enriched mammospheric cells have a stronger tumorigenic capacity than adherent cells in vivo tumorigenesis. DC vaccination using BSC lysates elicited specific T-cell responses against BSCs. DC vaccination stimulated Th1 response and induced significant IFN-γ production which is positively correlated with the number of cytotoxic T lymphocytes (CTLs) stimulated. Strikingly, using BSC breast cancer model, we demonstrate that vaccination with CTL stimulated DCs pulsed with enriched mammospheric cells lysates, but not pulsed with adherent cells lysates, prolonged survival in animals bearing BSC breast cancer tumors. Therefore, these proof-of-concept results confirmed CD44⁺/CD24^-/CD133⁺ mammospheric cells have stem cells property and DC immunization with BSCs generates superior antitumor immunity which may accelerate development of BSC-specific immunotherapies and cancer vaccines.