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

Abstract

Keywords: antitumor immunity, cancer stem cell, dendritic cell, metastasis, vaccine Abbreviations: ALDH, aldehyde dehydrogenase; CSC, cancer stem cell; CSC-DC, CSC lysate-pulsed dendritic cell; DC, dendritic cell; H-DC, heterogeneous, unsorted tumor cell lysate-pulsed dendritic cell; RT, radiation therapy; qRT-PCR, real time quantitative PCR.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 ALDH high CSC frequency in primary tumors. Direct targeting of CSCs was demonstrated by the specific binding of IgG produced by ALDH high CSC-DC vaccineprimed B cells to ALDH high 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.

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

“…22 Abovementioned findings indicated that ALDH1 isoenzymes are also possible therapeutic targets for melanoma. At the same time, Lu et al 23 reported targeting murine MSC via dendritic-cell (DC) vaccination using DCs pulsed with ALDH bright cell lysates, which significantly inhibited tumor growth as compared with DCs pulsed with either ALDH dim or whole tumor lysates. Moreover, in serum from these mice IgG antibodies that bound ALDH bright cells and mediated their complement-dependent lysis were found.…”

“…As mentioned above these antibodies analyzed in animal models were able to eliminate ALDH1 positive melanoma stem cells by antibody dependent cell cytotoxicity. 23 …”

Immunotherapy for Head and Neck Squamous Cell Carcinoma

“…Interestingly, the absolute number of Tregs was also decreased after vaccination 66 . Additionally, a recent study in a murine model looking at a cancer stem cell (CSC) targeted dendritic cell vaccination showed significantly reduced growth of subcutaneous tumors, increased survival, and decreased pulmonary metastasis 67 .…”

Stem cell technology and engineering for cancer treatment

“…Cancer antigens could be loaded onto DCs by nano-sized carriers including nanoparticles or nanoemulsions (Park et al, 2013). Studies on mice have shown DCs primed by CSCs antigens effectively induced immune response to tumor cells and prolonged survival (Lu et al, 2015;Ning et al, 2012;Xu et al, 2009). Treatment with DCs loaded with CSCs-derived antigen induced a tumorspecific immune response stronger than that induced by DCs loaded with normal tumor cells (Dillman et al, 2012;Jachetti et al, 2013).…”

“…DCs are then loaded with cancer antigens by various ways and reinfused into patient (Figure 4). Cancer antigens can be generated from tumor lysates (Yu et al, 2004), apoptotic bodies (Labarriere et al, 2002), peptides (Rosalia et al, 2013), tumor RNAs (Kalady et al, 2004), and tumor-derived exosomes (Mahaweni et al, 2013). Cancer antigens could be loaded onto DCs by nano-sized carriers including nanoparticles or nanoemulsions (Park et al, 2013).…”