CAR-T cells therapies turn out to be a breakthrough, particularly for B-cell malignancies. However, its application in solid tumor remains a challenge. The main limitations are: few highly specific tumor associated antigen (TAA), low T cell penetration and an immune-suppressive tumor microenvironment (TME). Thus, our aim was to develop a new immunotherapeutic strategy against HLA-G, an immune-tolerogenic molecule involved in tumor immune escape, frequently upregulated on tumor cells. HLA-G is a CMH-Ib molecule and exerts its immuno-inhibitory activity through specific binding with two inhibitory receptors, ILT2 and ILT4, leading to the inhibition of all immune cell subsets and the induction of suppressive immune cells. HLA-G was recently identified as an ICP molecule, could be highly neo-expressed in cancer, i.e.: ccRCC (98%) and associated with malignant transformation. HLA-G is found on tumor cells and is rarely observed in healthy tissues defining it as a remarkable TAA. RNAseq analyses show that HLA-G is a far better tumor specific antigen than PD-L1. However, no immunotherapy against HLA-G-expressing tumors has been developed. Indeed, neither stimulatory functions nor cellular responses directed against allogeneic HLA-G have been reported.
Highly specific antibodies against HLA-G, generated by our team, strongly bind to multiple HLA-G isoforms and their scFv were used to develop 3rd generation chimeric antigen receptors (CARs).
Anti-HLA-G CAR-T were specifically cytotoxic for HLA-G expressing target cells (K562-HLA-G1 and Jeg-3 cell lines), with resulting IFNg secretion and activation phenotype and also inducing a long-term T effector memory phenotype. Finally, in vivo assays demonstrated that anti-HLA-G CAR-T cells had strong anti-tumor activity controlling tumor progression up-to 50 days of experiment.
We report here for the first time CAR-T cells specifically targeting HLA-G expected to disrupt the tumor micro-environment related to HLA-G and solid tumors.
Invectys (Paris, France).
Invectys (Paris, France).
The author has declared no conflicts of interest.