Induction of tumor-specific CD8+ cytotoxic T lymphocytes from naive 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 XCR1(+)CD141(+) appear to be induced by tumor-derived soluble factors or dexamethasone, while the immunogenic DCs usually express XCR1(+)CD141(+) 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 XCR1(+)CD141(+) 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 naive 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.