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 emergence 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. Acquired resistant models to a high-affinity-CEA-targeted TCB exhibit a reduction of CEA levels due to transcriptional 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. [Display omitted] • Different mechanisms of resistance to TCBs emerge depending on the targeted tumor antigen • Acquired resistant cells to a TCB targeting CEACAM5 exhibit reduced antigen expression • 5-AZA overcomes resistance to CEACAM5-TCB by recovering the expression of CEACAM5 • Resistance to HER2-TCB in contrast is mediated by downmodulation of IFN-γ signaling Despite the success of immunotherapy, cancer patients eventually progress due to the emergence of resistance. Martínez-Sabadell et al. show that different mechanisms of acquired resistance to T cell engaging bispecific antibodies emerge depending on the selected tumor antigen. These data will help to anticipate mechanisms and approaches to tackle resistances. [ABSTRACT FROM AUTHOR]