Therapy-induced senescence upregulates antigen presentation machinery and triggers anti-tumor immunity in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy often curable only by using intensive chemotherapy. Nonetheless, resistance/early relapses are frequent, underscoring the need to investigate the molecular events occurring shortly after chemotherapy. Therapy-induced senescence (TIS) is a fail-safe tumor suppressive mechanism that may elicit immune-mediated responses contributing to senescent cell clearance. Yet, TIS functional role in AML eradication and immune surveillance early post-chemotherapy remains ill-defined. By combining transcriptional and cellular-based evaluation of senescence markers in AML patient samples, we found upregulation of senescence-associated genes and interferon gene categories with concomitant induction of HLA class I and class II molecules, pointing to a causal link between TIS and leukemia immunogenicity. Consistently, senescence-competent AML samples activated autologous CD4+ and CD8+ T cells and improved leukemia recognition by both T-cell subsets. Lastly, the anti-leukemic activity of Immune Checkpoint Blockades (ICBs) was enhanced upon senescence engagement in AML. Altogether, our results identify senescence as a potent immune-related anti-leukemic mechanism that may rapidly translate into innovative senescence-based strategies to prevent AML relapse.

Recent insights into the crosstalk between senescent cells and CD8 T lymphocytes

“…The activation of IFN signaling is propaedeutic for MHC-I overexpression and subsequent CD8 T cell mediated killing 16 . These results are further supported by a recent preprint by Di Micco and colleagues who also report high levels of MHC-I in chemotherapy-treated primary human senescent leukemia cells 17 . Also, these findings are aligned with previous data from the Van Deursen and Schmitt labs placing macrophages at the interface between stressed/senescent cells and CD8 T cell mediated clearance 18,19 .…”

Therapy-induced cellular senescence: Potentiating tumor elimination or driving cancer resistance and recurrence?

“…Combining Abemaciclib with anti-PD-L1, an immune checkpoint inhibitor, results in further tumor suppression [211]. Senescent AML cells triggered by cytosine arabinoside also display increased MHC expression, effectively activating T cell proliferation [212]. This effect can be enhanced by the anti-PD-1 antibody Nivolumab [212].…”

“…Senescent AML cells triggered by cytosine arabinoside also display increased MHC expression, effectively activating T cell proliferation [212]. This effect can be enhanced by the anti-PD-1 antibody Nivolumab [212]. These synergies suggest a potential combination strategy of senescence-inducing therapies with immune checkpoint inhibitors to achieve enhanced cancer control.…”