Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells.

The inability to target cancer stem cells (CSC) may be a significant factor contributing to treatment failure. We have developed a strategy to target the CSC populations in melanoma and squamous cell carcinoma using CSC lysate-pulsed dendritic cells (DCs). The CSC-DC vaccine was administered in the adjuvant setting after localized radiation therapy of established tumors. Using mouse models we demonstrated that DCs pulsed with CSCs enriched by virtue of their expression of the CSC marker ALDH (termed CSC-DC) significantly inhibited tumor growth, reduced development of pulmonary metastases and prolonged survival. The effect was associated with downregulation of chemokine (C-C motif) receptors CCR7 and CCR10 in tumor cells and decreased expression of the chemokine (C-C motif) ligands CCL21, CCL27 and CCL28 in lung tissue. The CSC-DC vaccine significantly reduced ALDHhigh CSC frequency in primary tumors. Direct targeting of CSCs was demonstrated by the specific binding of IgG produced by ALDHhigh CSC-DC vaccine-primed B cells to ALDHhigh CSCs, resulting in lysis of these target CSCs in the presence of complement. These data suggest that the CSC-DC vaccine approach may be useful in the adjuvant setting where local and systemic relapse are high after conventional treatment of cancers.

Effects of tumor irradiation on host T-regulatory cells and systemic immunity in the context of adoptive T-cell therapy in mice.

In this study, we used a murine D5 melanoma model to study the effects of local tumor irradiation on the therapeutic efficacy of adoptive T-cell therapy. Tumor irradiation was delivered in 5 daily fractions (8.5 Gy) to subcutaneous tumors on days 7-11 after tumor inoculation. After the last radiation dose, activated tumor-draining lymph node cells were transferred intravenously followed by intraperitoneal IL-2 administration. Tumor irradiation alone had no significant effect on tumor growth; however, it synergistically enhanced the therapeutic efficacy of T-cell therapy. For 2 days after tumor irradiation there was a significant reduction in T cells, B cells, and CD11c(+) dendritic cells in both the tumor microenvironment and the systemic lymphoid compartments. By days 4-6 after irradiation, the relative reduction in the number of Treg cells within the tumor and the systemic compartments was greater than the reduction in conventional T cells. Furthermore, the suppressive function of the Tregs was significantly impaired in irradiated versus untreated mice. Using effector T cells derived from congenic mice, we found that local tumor irradiation resulted in increased proliferation of donor T cells within the tumor and the systemic lymphoid compartments. Radiation was associated with increased expression of the effector cytokines IFN-γ and TNF-α by donor and host CD4(+) and CD8(+) T cells. Altogether, our data indicate that local tumor irradiation has a distinct modulatory effect on Tregs and can enhance systemic antitumor immunity associated with adoptive T-cell therapy.

Cancer stem cell vaccination confers significant antitumor immunity.

Most studies of cancer stem cells (CSC) involve the inoculation of cells from human tumors into immunosuppressed mice, preventing an assessment on the immunologic interactions and effects of CSCs. In this study, we examined the vaccination effects produced by CSC-enriched populations from histologically distinct murine tumors after their inoculation into different syngeneic immunocompetent hosts. Enriched CSCs were immunogenic and more effective as an antigen source than unselected tumor cells in inducing protective antitumor immunity. Immune sera from CSC-vaccinated hosts contained high levels of IgG which bound to CSCs, resulting in CSC lysis in the presence of complement. CTLs generated from peripheral blood mononuclear cells or splenocytes harvested from CSC-vaccinated hosts were capable of killing CSCs in vitro. Mechanistic investigations established that CSC-primed antibodies and T cells were capable of selective targeting CSCs and conferring antitumor immunity. Together, these proof-of-concept results provide a rationale for a new type of cancer immunotherapy based on the development of CSC vaccines that can specifically target CSCs.