Optimisation of the anti-tumoral immune responses in rhabdoid tumors : a translational approach

Rhabdoid tumors (RTs) are rare but highly malignant tumors that occur primarily in early childhood. These tumors were originally described in soft tissues, but are most commonly seen in the CNS where they are called atypical teratoid rhabdoid tumors (AT-RT). Despite therapeutic advances, the prognosis of patients with RT remains poor with an overall survival of barely 40%, regardless of the anatomical location. This poor prognosis suggests the urgent need to find new and better treatments. In collaboration with the SIRIC Teams lead by Franck Bourdeaut and Joshua Waterfall, we have recently shown that RT can be targeted by immunotherapy (Leruste et al, Cancer Cell. 2019), although it is considered one of the tumors with low mutational load and therefore not immunogenic. Currently, our work involves i) deciphering the nature of antigens recognized by immune cells and ii) investigating translational combinatorial immunotherapies for RT.

To determine tumor-derived antigens, we analyze tumor cells from patient-derived cell lines or xenografts (PDX) and tumor-infiltrating T lymphocytes by multiparametric assays involving mass spectrometry, a combinatorial peptide library and in silico structural predictions. The resulting peptide candidates will be synthesized and those that stimulate a better tumor-specific response will be selected. In addition, the T cell receptor (TCR) of T cells that recognize these antigens will be used to generate functional TCR cells for adoptive cell therapy.

However, to mount an effective anti-tumor immune response, tumor-specific T cells must be properly activated and tumor-associated immunosuppressive cells must be inactivated. The second objective of this project is to target pro-tumor populations and block immunosuppressive molecules. The scRNAseq analysis of the immune infiltrate of human and mouse RT allowed us to identify some drug targets that are involved in the reprogramming of pro-tumor myeloid cells and the reinvigoration of cytotoxic T cells. The combination of different drug targets is being tested in vivo using a well-established RT mouse model with promising results.

Taken together, the results of this unique and collaborative effort will be transformative and should help optimize the treatment of RT, generating immunotherapies that will decrease the side effects associated with current treatments.

This project is led by Valeria MANRIQUEZ (Post-doc) in the context of the Thematic A.

Collaborators :

Franck BOURDEAULT et Joshua WATERFALL (U830) ; Celio POUPONOT (UMR3347 / U9021), (Institut Curie)

Roberto MALLONE (Institut Cochin), Joelle VINH (ESPCI), Daron STANDLEY (Université d’Osaka, Japon) et Christian HINRICHS (NIH, USA)