Targeting leukemia by CD1c-restricted T cells specific for a novel lipid antigen

Abstract

A subset of CD1c-restricted T lymphocytes exhibits strong reactivity against leukemia cells. These T cells recognize methyl-lysophosphatidic acid (mLPA), a novel lipid antigen produced by acute leukemia cells. Considering that CD1c-restricted T cells display efficacious anti-leukemia activities in a mouse model, this lipid antigen thus represents a novel target in the immunotherapy of hematological malignancies.

Keywords: CD1; autoreactivity; immunesurveillance; immunotherapy; leukemia; lipid antigens.

Figure 1.

Targeting leukemia by CD1c-restricted T cells specific for a novel lipid antigen. (A) CD1c self-reactive T cells recognize the self-lipid antigen methyl-lysophospatidic acid (mLPA), which is upregulated by oncogenic metabolic processes in malignant cells (acute myeloid or lymphocytic leukemias), compared with normal monocytes and B cells. (B) mLPA-specific T cell receptor (TCR) genes are cloned into lentivirus (LV) vectors that can be utilized to efficiently transfer the antigen-specificity into polyclonal T cells. LV vector structure: LTR/ΔU3, long terminal repeats, with deletions; ψ, packaging sequence; RRE, reverse response element; SFFV prom, Spleen Focus Forming Virus promoter; IRES, internal ribosome entry site sequence; WPRE, post-translational regulatory element of Woodchuck Hepatitis Virus. (C) T cells from acute leukemia patients are expanded and transduced ex vivo with the LV carrying mLPA-specific TCR genes, which redirects T cells against the leukemia target upon adoptive transfer into the patients.