AI Article Synopsis
- dMMR tumors respond well to immune checkpoint inhibitors, but resistance can hinder treatment success.
- The study compared the effects of an α-PD-L1 antibody and the CDK4/6 inhibitor abemaciclib in mouse models, finding that abemaciclib significantly improved survival compared to α-PD-L1.
- The treatment with abemaciclib led to increased immune cell activity, reduced T cell exhaustion, and higher expression of DNA repair genes, suggesting it may be a suitable option for dMMR patients who can’t use ICIs.
Article Abstract
Mismatch repair-deficient (dMMR) tumors show a good response toward immune checkpoint inhibitors (ICI), but developing resistance impairs patients' outcomes. Here, we compared the therapeutic potential of an α-PD-L1 antibody with the CDK4/6 inhibitor abemaciclib in two preclinical mouse models of dMMR cancer, focusing on immune-modulatory effects of either treatment. Abemaciclib monotherapy significantly prolonged overall survival of Mlh1 and Msh2 mice (Mlh1: 14.5 wks . 9.0 wks (α-PD-L1), and 3.5 wks (control); Msh2 : 11.7 wks . 9.6 wks (α-PD-L1), and 2.0 wks (control)). The combination was not superior to either monotherapy. PET/CT imaging revealed individual response profiles, with best clinical responses seen with abemaciclib mono- and combination therapy. Therapeutic effects were accompanied by increasing numbers of tumor-infiltrating CD4/CD8 T-cells and lower numbers of M2-macrophages. Levels of T cell exhaustion markers and regulatory T cell counts declined. Expression analysis identified higher numbers of dendritic cells and neutrophils within tumors together with high expression of DNA damage repair genes as part of the global stress response. In Mlh1 tumors, abemaciclib suppressed the PI3K/Akt pathway and led to induction of /. The immune-modulatory potential of abemaciclib renders this compound ideal for dMMR patients not eligible for ICI treatment.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278458 | PMC |
| http://dx.doi.org/10.1080/2162402X.2022.2094583 | DOI Listing |
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