Therapy-induced senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Abstract Immune checkpoint inhibitors (ICI) invigorate immune cell functions and are effective against many cancer types. However, the potential of ICI may be limited in situations where immune cell fitness is impaired. Here, we show that the efficacy of αPD-L1-based cancer immunotherapies is compromised by the accumulation of senescent cells in mice previously exposed to sublethal irradiation or injected with doxorubicin. Similarly, we observed that the efficacy of the combination of a αCTLA-4 antibody with radiotherapy is diminished in previously irradiated mice. In both models, resistance to immunotherapy was associated with a decrease in the accumulation and activation of CD8 T cells within tumors. Elimination of senescent cells by the injection of the senolytic drug ABT263, weeks before treatments, restored immune homeostasis within the tumor micro-environment (TME) and increased mice survival in both models. Using single-cell transcriptomic analysis, we observed that the injection of ABT263 reverses the exacerbated immunosuppressive profile of myeloid cells in the TME of previously irradiated mice. These myeloid cells, when purified from established tumors, were responsible for impaired CD8 T cell proliferation in vitro. Our study shows that cancer therapies, by inducing senescence, favor the formation of an immunosuppressive TME, which can alter the efficacy of ICI. The use of senolytic drugs before ICI may constitute an interesting pharmacological approach to improve the effectiveness of cancer immunotherapies.