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

Our plain-English summary of Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor, by T. Ge, A.L. Phung, G. Jhala, et al (Clinical & Translational Immunology, 2022).

The study

• Authors: T. Ge, A.L. Phung, G. Jhala, P. Trivedi, N. Principe, D.J. De George, E.G. Pappas, S. Litwak, L. Sanz-Villanueva, T. Catterall, S. Fynch, L. Boon, T.W. Kay, J. Chee, B. Krishnamurthy, H.E. Thomas
• Journal: Clinical & Translational Immunology
• Published: 2022;11(11):e1425
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.

In plain English

This was a laboratory animal experiment in mice. Female nonobese diabetic (NOD) mice aged 7–8 weeks were given three intraperitoneal doses of anti-PD-L1 antibody, which caused rapid diabetes: 72.7% (8/11) became diabetic within 2 weeks, with onset beginning at day 9. Islets of treated mice showed increased MHC class I on beta cells, more CD45+ immune cells, more CD4+ and CD8+ T cells and increased T cell proliferation, and more IGRP206-214-specific CD8+ T cells in lymphoid organs. The JAK1/JAK2 inhibitor LN3103801, given by oral gavage, prevented the islet and T cell changes and reduced the number of IGRP206-214-specific CD8+ T cells. Given before anti-PD-L1, no treated mouse became diabetic during treatment and 66.7% (4/6) were still nondiabetic 2 weeks after stopping, versus 83.3% (5/6) diabetic on vehicle. Started after hyperglycaemia began, it reversed diabetes in 55.6% (5/9). In BALB/c mice carrying transplanted AB1-HA mesothelioma tumours, the authors reported similar median survival when the inhibitor followed checkpoint blockade (24 days vs 26 days, P = 0.6), with no statistically significant difference detected in this single tumour model, while concurrent treatment abrogated antitumour responses. The authors concluded the study provides preclinical validation for testing JAK inhibitors in checkpoint inhibitor-induced diabetes.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal (mouse) experimental study, with a transplantable tumour model
• Who was studied: Female NOD/Lt mice, mostly 7-8 weeks old (some experiments used 9- and 10-week-old mice), bred at St Vincent's Institute; female BALB/c.J mice 8-10 weeks old were used for the tumour experiments in Perth, Australia
• Exposure: Anti-PD-L1 antibody (three doses of 250 µg, 2-day intervals), anti-PD-1 in one experiment, and the JAK1/JAK2 selective inhibitor LN3103801 (3 mg/kg twice daily by oral gavage for 14 days); in the tumour model, anti-CTLA-4 plus anti-PD-L1 checkpoint blockade
• Main results:
  • Anti-PD-L1 alone: 72.7% (8/11) of NOD mice became diabetic within 2 weeks, starting at day 9
  • Anti-PD-L1 significantly increased the proportion of CD45+ immune cells in islets compared with PBS-treated controls (PBS N = 14, anti-PD-L1 N = 12)
  • JAK1/JAK2 inhibitor given before anti-PD-L1 prevented MHC class I upregulation on beta cells and infiltration of CD45+ immune cells into islets
  • JAK1/JAK2 inhibitor treatment reduced, in mice given anti-PD-L1, the number of IGRP206-214-specific CD8+ T cells in peripheral lymphoid organs and pancreatic lymph node compared with vehicle
  • JAK1/JAK2 inhibitor started before anti-PD-L1: 83.3% (5/6) of vehicle mice became diabetic in 2 weeks; no inhibitor-treated mouse became diabetic during treatment and 66.7% (4/6) remained nondiabetic 2 weeks after stopping
  • JAK1/JAK2 inhibitor started after anti-PD-L1 completion: 87.5% (7/8) of vehicle mice became diabetic versus 75% (6/8) of inhibitor-treated mice remaining diabetes-free
  • Reversal after diabetes onset: all vehicle-treated mice stayed hyperglycaemic, while hyperglycaemia was reversed in 55.6% (5/9) of inhibitor-treated mice
  • In the mesothelioma tumour model, JAK1/JAK2 inhibitor given at the same time as checkpoint blockade reduced median survival compared with checkpoint blockade alone: 21.5 days versus 23 days, P = 0.0081
  • With checkpoint blockade alone, 4/10 mice showed tumour regression or growth delay, whereas no mouse (0/10) responded in the concurrent JAK1/JAK2 inhibitor plus checkpoint blockade group
  • JAK1/JAK2 inhibitor given after completion of checkpoint blockade: median survival 24 days versus 26 days for checkpoint blockade alone (P = 0.6)
• The authors' conclusion: The authors concluded that a JAK1/JAK2 inhibitor can prevent and reverse anti-PD-L1-induced diabetes by blocking IFN-gamma and common gamma chain cytokine activities, providing preclinical validation for its use in checkpoint inhibitor-induced diabetes
• Limitations the authors state:
  • Only one tumour model of response to immune checkpoint blockade was tested, and the authors state more work is needed with other tumour types
  • The authors note the effect of checkpoint blockade in this tumour model is modest
  • The authors note that cell types other than T cells and beta cells, not studied here, may also be involved

Topics

Medical terms in this study, explained in our Lexicon: checkpoint inhibitors, Immune-Related Adverse Events, PD-L1, Mesothelioma, Cytokine.

Related studies

• Pemetrexed-Induced Rash May Be Prevented by Supplementary Corticosteroids — T. Sakurada, S. Kakiuchi, et al. (2015)
• Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma — P. Indovina, E. Marcelli, et al. (2014)
• Recent Advances of Immune Checkpoint Inhibition and Potential for (Combined) TIGIT Blockade as a New Strategy for Malignant Pleural Mesothelioma — S. Rovers, A. Janssens, et al. (2022)
• Immune checkpoint inhibition in malignant mesothelioma: Does it have a future? — A.S. Mansfield (2017)
• Immune Checkpoint Inhibition for Unresectable Malignant Pleural Mesothelioma — W. Cui, S. Popat (2021)
• Immune checkpoint inhibitors in non-small cell lung cancer (NSCLC): Approaches on special subgroups and unresolved burning questions — J. Remon, N. Vilariño, et al. (2018)

Browse return to medical research.