Immune checkpoint inhibitors (ICBs) such as anti-PD-L1 and anti-CTLA4 are at the forefront of cancer treatment in various cancers. However, the response rate to ICBs in metastatic breast cancer remains to be suboptimal. Using immune profiling, gene expression studies, and in vitro and in vivo experiments, researchers from the Netherlands Cancer Institute, Amsterdam, revealed a collaborating axis between T-cells and eosinophils and found that adding recombinant IL-33 (activator of eosinophils) to ICBs significantly improved the ICB efficacy in breast cancer. These findings were published in Cancer Cell.
For this study, metastatic triple-negative breast cancer (TNBC) patients (n=111) enrolled in the phase II TONIC trial were profiled pre- and post-anti-PD1 treatment. This immuno-profiling revealed that ICB response is significantly associated with a systemic increase in the level of eosinophils. Researchers were able to validate these findings in metastatic non-small cell lung cancer and in early colon cancer. Additionally, an increase in intra-tumoral eosinophil markers along with activated CD8+ T-cell genes was seen in responders. These observations clearly establish a link between eosinophils and activated T-cells in relation to the efficacy of ICB.
Using a breast cancer mouse model, researchers showed that ICB synergised with cisplatin resulting in improved survival. This was associated with a systemic and intra-tumoral increase of eosinophils and activated effector T cells. Next, they investigated the link between eosinophil accumulation and ICB benefit by systematically analysing metastasis-bearing mouse models across time points. This analysis revealed IL-5 as a key driver of ICB-induced eosinophil induction and that this could be inhibited using antibody-mediated blockade of IL-5. Further analysis showed that IL-33 expression was needed for eosinophils to infiltrate tumours and its blockade reduced eosinophil infiltration and, thus, the therapeutic effect of ICBs.
Researchers validated these observations in a mouse model of breast cancer where combined treatment of ICBs with recombinant-IL33 increased the response rate to ICBs. As such, these findings shed some light on the mechanistic basis of ICB activity and further advance our current understanding of immunotherapy.
Reference
Top
