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Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor. | LitMetric

AI Article Synopsis

  • Immune checkpoint inhibitors can effectively treat cancer but are linked to immune-related side effects, including type 1 diabetes (T1D), prompting researchers to explore preventive treatments like JAK1/JAK2 inhibitors.* -
  • In experiments with nonobese diabetic mice, JAK1/JAK2 inhibitors successfully prevented and even reversed diabetes caused by PD-L1 blockade, inhibiting harmful immune cell activity in the pancreas.* -
  • The study demonstrates that JAK1/JAK2 inhibitors might be a viable option for managing diabetes resulting from cancer therapy, without compromising the anti-tumor effectiveness in other models.*

Article Abstract

Objectives: Immune checkpoint inhibitors have achieved clinical success in cancer treatment, but this treatment causes immune-related adverse events, including type 1 diabetes (T1D). Our aim was to test whether a JAK1/JAK2 inhibitor, effective at treating spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice, can prevent diabetes secondary to PD-L1 blockade.

Methods: Anti-PD-L1 antibody was injected into NOD mice to induce diabetes, and JAK1/JAK2 inhibitor LN3103801 was administered by oral gavage to prevent diabetes. Flow cytometry was used to study T cells and beta cells. Mesothelioma cells were inoculated into BALB/c mice to induce a transplantable tumour model.

Results: Anti-PD-L1-induced diabetes was associated with increased immune cell infiltration in the islets and upregulated MHC class I on islet cells. Anti-PD-L1 administration significantly increased islet T cell proliferation and islet-specific CD8 T cell numbers in peripheral lymphoid organs. JAK1/JAK2 inhibitor treatment blocked IFNγ-mediated MHC class I upregulation on beta cells and T cell proliferation mediated by cytokines that use the common γ chain receptor. As a result, anti-PD-L1-induced diabetes was prevented by JAK1/JAK2 inhibitor administered before or after checkpoint inhibitor therapy. Diabetes was also reversed when the JAK1/JAK2 inhibitor was administered after the onset of anti-PD-L1-induced hyperglycaemia. Furthermore, JAK1/JAK2 inhibitor intervention after checkpoint inhibitors did not reverse or abrogate the antitumour effects in a transplantable tumour model.

Conclusion: A JAK1/JAK2 inhibitor can prevent and reverse anti-PD-L1-induced diabetes by blocking IFNγ and γc cytokine activities. Our study provides preclinical validation of JAK1/JAK2 inhibitor use in checkpoint inhibitor-induced diabetes.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618467PMC
http://dx.doi.org/10.1002/cti2.1425DOI Listing

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