Unconventional Tumor Epitopes, Antigen Presentation and T-cell Engineering

Research summary

Mutation-associated neoepitopes play a major role in the response to immune checkpoint inhibitors and are currently used in cancer vaccine and T cell-based strategies. However, the development of these personalized approaches remains complex and poorly adapted to large numbers of tumors with a low mutational burden (TMB). There is therefore a major need to identify new families of tumor-specific antigens shared across patients to propose “off-the shelf” immunotherapies, especially in tumors characterized by a low TMB. Furthermore, amplification of the cellular immunity and epitope spreading are essential elements for the success of a vaccine strategy. It is now established in different anti-tumor vaccine approaches that the therapeutic response in patients is linked to the activation of cytotoxic T cells (CTL) recognizing not only the vaccine antigens, but also multiple others endogenous tumor antigens. The epitope spreading is the consequence of capture and presentation by tumor infiltrating dendritic cells (DCs) of tumor antigens released from tumor cells that were killed by anti-vaccine antigen CTL. In this context, DCs are highly specialized in the uptake, processing, and presentation of antigens, and many studies have identified the cDC1 subset as specialized in tumor antigen cross-presentation.

The team is thus focused on the identification and validation of shared neoepitopes derived from Human Endogenous Retroviruses (HERVs) and from alternative translational control of oncogenes. Several translational programs are developed as well as innovative approaches to improve the therapeutic efficacy of cancer vaccines by increasing cross-presentation by DCs and epitope spreading. Finally, we are also working on optimizing T cell receptor engineering to enhance the parameters associated with T cell activation against tumor cells expressing low-density targeted epitopes.