Chronic Antigen Stimulation in Solid Tumors Induces T Cell Exhaustion and Limits Efficacy of T Cell Bispecific Therapies

T cell bispecific antibodies (TCBs) have demonstrated promising results in patients with solid tumors. However, the underlying immunological and molecular mechanisms influencing these clinical outcomes require in depth evaluation. T cell exhaustion, a state induced by prolonged antigen exposure, is known to undermine T cell-based immunotherapies, though its specific impact on TCB efficacy remains unclear. In this study, we assessed the effectiveness of TCBs on tumor-specific T cells, focusing on their functional status. Utilizing a fully immunocompetent mouse model with a solid tumor expressing an immunogenic antigen, we showed that tumor-specific T cells acquire an exhausted phenotype and fail to expand under TCB treatment. By employing both mouse and human tumor-specific T cells in vitro , our study established that chronically stimulated tumor-specific T cells show impaired response to TCB treatment. The comparison of TCB efficacy in T cell-inflamed tumors with immunogenic antigens versus non-inflamed tumors with low antigen presence in mice revealed TCB success in solid tumors is more reliant on T cell functional fitness than on their abundance before treatment. The data also indicate that solid tumors with elevated levels of both, intratumoral regulatory T cells, and T cells expressing co-inhibitory receptors, show diminished responses to TCB therapy, aligning with similar observations described in hematological cancers. These findings highlight the critical role of T cell exhaustion due to chronic antigen exposure and illustrate that exhausted tumor-specific T cells are likely not the driver population redirected by TCBs for tumor elimination. Our research highlights the importance of maintaining T cell fitness and preventing T cell exhaustion to improve TCB therapy outcomes. This may help better identify patient populations with solid tumors that could benefit from TCB treatments most in clinical settings.