The main objective of this project is to demonstrate that the HLA-G molecule can be used to target treatments against a variety of tumors, particularly those lacking specific tumor antigens (TSA).

Project Rationale: HLA-G has two key characteristics that make it attractive for antitumor therapy:

Immunosuppressive function: HLA-G acts as an immune checkpoint, blocking cytotoxic immune cells that are anti-tumor, thereby allowing tumor cells to evade immune surveillance.
Selective expression: HLA-G is primarily a fetal molecule, with virtually no expression in adults. However, it is commonly re-expressed in many solid tumors.
The restricted expression of HLA-G in pathological tissues, mainly tumor cells, makes it an appealing target for therapeutic targeting. This characteristic will be exploited in the project. Indeed, a molecule that is specifically expressed by a tumor is an ideal TSA, enabling targeted treatment with minimal side effects on healthy cells. Unfortunately, tumor-specific antigens are rare, costly to develop, and, for most tumors, none exist to date.

HLA-G, expressed in the majority of tumor types—both common and rare—represents an excellent candidate for a multi-tumor TSA.

Project Methodology
The project will use microfluidic chips and 3D tumor avatars (tumor spheroids derived from patients with renal cancer) already established in the laboratory to evaluate the efficacy of BiTEs (Bi-Specific T-cell Engagers). One side of the BiTEs will target HLA-G as the addressing molecule, and the other side will target tumor-infiltrating cytotoxic cell antigens (T lymphocytes and NK cells).

Resources and Expertise
The project will build on the laboratory’s expertise in:

The HLA-G molecule and its functions in immunology and immuno-oncology, a subject the laboratory has studied for over 20 years.
The immune environment of renal tumors, particularly intratumoral cytotoxic cells.
Clinical expertise in immuno-urology-oncology from clinicians at St. Louis Hospital, Paris.
The project will employ advanced technologies, including spectral flow cytometry and 3D tumor avatars in microfluidic chips.

Conclusion
By using innovative technologies and relying on strong expertise, the project aims to develop new therapeutic strategies applicable to a broad range of cancers expressing HLA-G.