Induction of Tumor-specific CD8 Cytotoxic T Lymphocytes from Naïve Human T Cells by Using Mycobacterium-derived Mycolic Acid and Lipoarabinomannan-stimulated Dendritic Cells

The main effectors in tumor control are the class I MHC molecule-restricted CD8 cytotoxic T lymphocytes (CTLs). Tumor-specific CTL induction can be regulated by dendritic cells (DCs) expressing both tumor-derived epitopes and co-stimulatory molecules. Immunosuppressive tolerogenic DCs, having down-regulated co-stimulatory molecules, are seen within the tumor mass and can suppress tumor-specific CTL induction. The tolerogenic DCs expressing down-regulated XCR1CD141 appear to be induced by tumor-derived soluble factors or dexamethasone, while the immunogenic DCs usually express XCR1CD141 molecules with a cross-presentation function in humans. Thus, if tolerogenic DCs can be reactivated into immunogenic DCs with sufficient co-stimulatory molecules, tumor-specific CD8 CTLs can be primed and activated in vivo. In the present study, we converted human tolerogenic CD141 DCs with enhanced co-stimulatory molecule expression of CD40, CD80, and CD86 through stimulation with non-toxic mycobacterial lipids such as mycolic acid (MA) and lipoarabinomannan (LAM), which synergistically enhanced both co-stimulatory molecule expression and interleukin (IL)-12 secretion by XCR1CD141 DCs. Moreover, MA and LAM-stimulated DCs captured tumor antigens and presented tumor epitope(s) in association with class I MHCs and sufficient upregulated co-stimulatory molecules to prime naïve CD3 T cells to become CD8 tumor-specific CTLs. Repeat CD141 DC stimulation with MA and LAM augmented the secretion of IL-12. These findings provide us a new method for altering the tumor environment by converting tolerogenic DCs to immunogenic DCs with MA and LAM from Mycobacterium tuberculosis.