MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors
Dominik Marschner, Martina Falk, Nora Rebeka Javorniczky, Kathrin Hanke-Müller, Justyna Rawluk, Annette Schmitt-Graeff, Federico Simonetta, Eileen Haring, Severin Dicks, Manching Ku, Sandra Duquesne, Konrad Aumann, David Rafei-Shamsabadi, Frank Meiss, Patrick Marschner, Melanie Boerries, Robert S. Negrin, Justus Duyster, Robert Zeiser, Natalie Köhler
Dominik Marschner, Martina Falk, Nora Rebeka Javorniczky, Kathrin Hanke-Müller, Justyna Rawluk, Annette Schmitt-Graeff, Federico Simonetta, Eileen Haring, Severin Dicks, Manching Ku, Sandra Duquesne, Konrad Aumann, David Rafei-Shamsabadi, Frank Meiss, Patrick Marschner, Melanie Boerries, Robert S. Negrin, Justus Duyster, Robert Zeiser, Natalie Köhler
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Research Article Inflammation Oncology

MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors

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.

Authors

Dominik Marschner, Martina Falk, Nora Rebeka Javorniczky, Kathrin Hanke-Müller, Justyna Rawluk, Annette Schmitt-Graeff, Federico Simonetta, Eileen Haring, Severin Dicks, Manching Ku, Sandra Duquesne, Konrad Aumann, David Rafei-Shamsabadi, Frank Meiss, Patrick Marschner, Melanie Boerries, Robert S. Negrin, Justus Duyster, Robert Zeiser, Natalie Köhler

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Figure 1

miR-146a deficiency increases irAE severity in anti–PD-1–treated mice.

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miR-146a deficiency increases irAE severity in anti–PD-1–treated mice. ...
WT or miR-146a–/– mice (n = 9–10 per group) were treated with LPS and anti–PD-1/isotype control antibody for 3 weeks as described. The lungs, liver, colon, and skin were isolated on day 22 after the first treatment for histopathological assessment. irAE grading was performed by an experienced pathologist blinded to the treatment groups. 0 = absent, 1 = mild, 2 = massive neutrophil/lymphocyte infiltration. Data were pooled from 2 independent experiments. Statistical significance was analyzed by Kruskal-Wallis test followed by 2-stage linear step-up procedure of Benjamini, Krieger and Yekutieli. Adjusted P value is depicted: **P < 0.01, ***P < 0.001. (A) Representative H&E staining of lung sections at original magnification ×200. Black arrows point towards inflammatory infiltrates. (B and C) Histopathology scores for neutrophil infiltration and lymphocyte infiltration into the lung. (D) Representative H&E staining of liver sections at original magnification ×200. Black arrows point towards inflammatory infiltrates. (E and F) Histopathology scores for neutrophil infiltration and lymphocyte infiltration into the liver. (G and H) Histopathology scores for neutrophil infiltration and lymphocyte infiltration into the colon. (I and J) Histopathology scores for neutrophil infiltration and lymphocyte infiltration into the skin. miR-146a, microRNA-146a, irAE, immune-related adverse event, PD-1, programmed cell death protein-1.