The target antigen determines the mechanism of acquired resistance to T cell-based therapies

Despite the revolution of immunotherapy in cancer treatment, patients eventually progress due to the emer-gence of resistance. In this scenario, the selection of the tumor antigen can be decisive in the success of the clinical response. T cell bispecific antibodies (TCBs) are engineered molecules that include binding sites to the T cell receptor and to a tumor antigen. Using gastric CEA(+)/HER2(+) MKN45 cells and TCBs directed against CEA or HER2, we show that the mechanism of resistance to a TCB is dependent on the tumor antigen. Ac-quired resistant models to a high-affinity-CEA-targeted TCB exhibit a reduction of CEA levels due to tran-scriptional silencing, which is reversible upon 5-AZA treatment. In contrast, a HER2-TCB resistant model maintains HER2 levels and exhibit a disruption of the interferon-gamma signaling. These results will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances.