M Messaoudene, TP Mourikis, J Michels, Y Fu, M Bonvalet, M Lacroix-Trikki, B Routy, A Fluckiger, S Rusakiewicz, MP Roberti, S Cotteret, C Flament, V Poirier-Colame, N Jacquelot, F Ghiringhelli, A Caignard, AMM Eggermont, G Kroemer, A Marabelle, M Arnedos, C Vicier, S Dogan, F Jaulin, S-J Sammut, W Cope, C Caldas, S Delaloge, N McGranahan, F André, L Zitvogel
BACKGROUND: Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancers (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy. PATIENTS AND METHODS: We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes (mLN) in early breast cancers after exposure to T cell bispecific antibodies (TCB) bridging CD3ε and HER2 or CEACAM5, before and after chemotherapy. HLA class I loss was assessed by whole exome sequencing and immunohistochemistry. 100 primary BC, 64 surrounding "healthy tissue" (HT) and 24 mLN related-parameters were analyzed. RESULTS: HLA loss of heterozygosity was observed in early BC, at a clonal and subclonal level and was associated with regulatory T cells and Tim3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3ε and HER2 or CEACAM5 could bypass MHC class I loss, partially rescuing T cell functions in mLN. CONCLUSION: TCB should be developed in BC to circumvent low MHC/peptide complexes.