Abstract PR03: Analysis of immune infiltrate identifies checkpoint blockade and TLR3 activation as efficient synergistic combination of immunotherapy in rhabdoid tumors

摘要: Rationale: Rhabdoid tumors (RTs) are highly aggressive cancers of infancy, arising from the central nervous system (atypical teratoid rhabdoid tumors, AT/RT) and other miscellaneous extracranial locations. RTs characterized by biallelic inactivation SMARCB1 tumor suppressor gene an otherwise stable genome. Prospective trials based on intensive multimodal therapies have led to few survivals, side effects a great matter concern. In prospect new therapeutic strategies, we analyzed immune contexture both human mouse RT. We subsequently explored in vivo targeting infiltrate order determine best immunotherapy strategy adapted specific context. Methods: first cohort samples, including AT/RT RT, immunohistochemistry, expression profiling, flow cytometry. parallel, performed same analyses obtained genetically engineered model (GEMM) RT Smarcb1flox/flox;Rosa26-CreERT2 previously established our lab, syngeneic heterotopic engraftment models that derived GEMM. After identifying targets, validated them preclinical Results: Despite well-established low mutational burden genome, found infiltrated cells lymphoid myeloid lineages. Tumor-infiltrating lymphocytes consist equal proportion CD4+ CD8+ T with regulatory cells. observed coexpress PD-1 TIM-3 activation/exhaustion markers, while express their respective ligands, i.e., PD-L1 Galectin 9. Consistently, blockade PD-1/PD-L1 pathway was able impair growth induced memory against second engraftment. Furthermore, combination anti-TIM-3 anti-PD-1 shows synergistic activity. context engraftment, expansion aberrant myelopoiesis corresponding suppressive transcriptomic signatures correlated chemokines known recruit such tumor-infiltrating were particularly intense constant feature consisting primarily macrophages protumoral phenotype. Targeting this TLR3 activation poly(I:C) potent antitumor effect. Combination had effect, leading complete regression around 90% treated mice. Conclusion: show here for time immune-infiltrated susceptible blockade, reprogramming Immunogenicity is surprising observation field pediatric tumors; hypothesize recognition initiated SMARCB1-dependent mechanism under investigation. Citation Format: Amaury Leruste, Zhi-Yan Han, Arnault Tauziede-Espariat, Pamela Caudana, Joshua J. Waterfall, Mamy Andrianteranagna, Christine Sedlik, Rodrigo Ramos, Sophie Viel, Celine Chauvin, Olivier Delattre, Eliane Piaggio, Franck Bourdeaut. Analysis identifies checkpoint as efficient [abstract]. In: Proceedings AACR Special Conference: Pediatric Cancer Research: From Basic Science Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Res 2018;78(19 Suppl):Abstract nr PR03.