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New drugs targeting B7-1/B7-H1/PD-1 interactions during tumor dormancy

Cell surface molecules of the B7 family play an essential role in positive and negative regulation of T-lymphocytes mediated immune response. Among them, B7-H1 (PD-L1) mainly inhibits T-cells via its interaction with the PD-1 receptor, and also surprisingly through direct interaction with B7.1 (CD80) molecule. B7.1 can also directly inhibit T-lymphocytes via CTLA4 inhibiting receptor.

Several experimental results suggest that the interaction between B7.1/B7-H1, B7-H1/PD-1, and B7.1/CTLA4 may have a role in limiting the antitumor immune response. We previously demonstrated that B7-1 and B7-H1 overexpressed by dormant tumor cells could promote the long-term persistence of these cells by inhibiting CTL-mediated immune responses and then allowing relapses. More generally, B7-1/B7-H1/PD1/CTLA4 interactions play a key role on immunoescape in many cancers. Blocking these interactions should favor eradication of tumor cells through host immune responses.

The objective of this project, done in collaboration with Pr B. Quesnel (SIRIC OncoLille, U837) is to develop small molecules blocking the interaction between B7-H1/B7-1 or B7-H1/PD-1 to allow to restoration of host anti-tumor immune response against dormant tumor cells.