Abstract
Immune checkpoint inhibitor (ICI) therapy has shown a significant benefit in the treatment of a variety of cancer entities. However, immune-related adverse events (irAEs) occur frequently and can lead to ICI treatment termination. MicroRNA-146a (miR-146a) has regulatory functions in immune cells. We observed that mice lacking miR-146a developed markedly more severe irAEs compared with WT mice in several irAE target organs in 2 different murine models. miR-146a-/- mice exhibited increased T cell activation and effector function upon ICI treatment. Moreover, neutrophil numbers in the spleen and the inflamed intestine were highly increased in ICI-treated miR-146a-/- mice. Therapeutic administration of a miR-146a mimic reduced irAE severity. To validate our preclinical findings in patients, we analyzed the effect of a SNP in the MIR146A gene on irAE severity in 167 patients treated with ICIs. We found that the SNP rs2910164 leading to reduced miR-146a expression was associated with an increased risk of developing severe irAEs, reduced progression-free survival, and increased neutrophil counts both at baseline and during ICI therapy. In conclusion, we characterized miR-146a as a molecular target for preventing ICI-mediated autoimmune dysregulation. Furthermore, we identified the MIR146A SNP rs2910164 as a biomarker to predict severe irAE development in ICI-treated patients.
Highlights
In the last decade, immune checkpoint inhibitors (ICIs) have dramatically changed the treatment algorithms of many solid tumors and hematological malignancies
Low-dose LPS was given to mimic the human situation, in which the immune system is typically not as naive as in mice under specific pathogen–free conditions. immune-related adverse events (irAEs) development was assessed by histopathology using a scoring system to quantify neutrophil and lymphocyte infiltration in different target organs that was established based on reports of the histopathological features of human irAEs [11, 12]
Treatment of miR-146a–/– mice with anti–PD-1 led to significantly more severe irAEs compared with WT mice treated with anti–PD-1, indicated by increased neutrophil and lymphocyte infiltration in the major irAE target organs, comprising the lungs (Figure 1, A–C), liver (Figure 1, D–F), colon (Figure 1, G and H), and skin (Figure 1, I and J)
Summary
Immune checkpoint inhibitors (ICIs) have dramatically changed the treatment algorithms of many solid tumors and hematological malignancies These antibodies inhibit negative regulatory molecules of the immune response, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), resulting in an enhanced T cell response against cancer cells. Grades 3–4 irAEs, in particular, are a major concern, since patients oftentimes have to permanently discontinue ICI therapy, receive immunosuppressive therapy, including corticosteroids, and are at high risk of death. To date, it is still largely unknown why some patients develop severe irAEs while other patients do not [5].
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