Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor–induced diabetes

Perdigoto, Ana Luisa; Deng, Songyan; Du, Katherine; Kuchroo, Manik; Burkhardt, Daniel; Tong, Alexander; Israel, Gary M.; Robert, Marie E.; Weisberg, Stuart P.; Kirkiles-Smith, Nancy C.; Stamatouli, Angeliki M.; Kluger, Harriet M.; Quandt, Zoe; Young, Arabella; Yang, Mei-Ling; Mamula, Mark J.; Pober, Jordan S.; Anderson, Mark S.; Krishnaswamy, Smita; Herold, Kevan C.

doi:10.1172/jci.insight.156330

Cited by 24 publications

(13 citation statements)

References 83 publications

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“…We observed here that IFNγ transcriptomic signature of sorted mouse primary beta cells was similar to previous observations on human beta cells [74], demonstrating the strength of our strategy. Confident with our protocol, we also characterized alpha and delta cells responses to IFNγ.…”

Section: Discussionsupporting

confidence: 86%

Pancreatic Islet Cells Response to IFNγ Relies on Their Spatial Location within an Islet

Burghgrave

Lourenço

Berthault

et al. 2022

Cells

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Type 1 diabetes (T1D) is an auto-immune disease characterized by the progressive destruction of insulin-producing pancreatic beta cells. While beta cells are the target of the immune attack, the other islet endocrine cells, namely the alpha and delta cells, can also be affected by the inflammatory milieu. Here, using a flow cytometry-based strategy, we compared the impact of IFNγ, one of the main cytokines involved in T1D, on the three endocrine cell subsets isolated from C57BL/6 mouse islets. RNA-seq analyses revealed that alpha and delta cells exposed in vitro to IFNγ display a transcriptomic profile very similar to that of beta cells, with an increased expression of inflammation key genes such as MHC class I molecules, the CXCL10 chemokine and the programmed death-ligand 1 (PD-L1), three hallmarks of IFNγ signaling. Interestingly, at low IFNγ concentration, we observed two beta cell populations (responders and non-responders) based on PD-L1 protein expression. Our data indicate that this differential sensitivity relies on the location of the cells within the islet rather than on the existence of two different beta cells subsets. The same findings were corroborated by the in vivo analysis of pancreatic islets from the non-obese diabetic mouse model of T1D, showing more intense PD-L1 staining on endocrine cells close to immune infiltrate. Collectively, our work demonstrates that alpha and delta cells are as sensitive as beta cells to IFNγ, and suggests a gradual diffusion of the cytokine into an islet. These observations provide novel insights into the in situ inflammatory processes occurring in T1D progression.

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Section: Discussionsupporting

confidence: 86%

Pancreatic Islet Cells Response to IFNγ Relies on Their Spatial Location within an Islet

Burghgrave

Lourenço

Berthault

et al. 2022

Cells

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“…The majority (95%) of T1DM patients have known antibodies to islet cells, compared with 40% of ICI-DM patients. [4][5][6] The pathogenesis of ICI-DM is not fully understood. It involves various cellular components of the immune system, as well as the microbiome, as reviewed.…”

Section: Introductionmentioning

confidence: 99%

Germline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors

Caulfield

Aizenbud

Perdigoto

et al. 2023

J Immunother Cancer

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BackgroundImmune checkpoint inhibitors (ICIs) have dramatically improved survival in patients with cancer but are often accompanied by severe immune-related adverse events (irAEs), which can sometimes be irreversible. Insulin-dependent diabetes is a rare, but life-altering irAE. Our purpose was to determine whether recurrent somatic or germline mutations are observed in patients who develop insulin-dependent diabetes as an irAE.MethodsWe performed RNA and whole exome sequencing on tumors from 13 patients who developed diabetes due to ICI exposure (ICI-induced diabetes mellitus, ICI-DM) compared with control patients who did not develop diabetes.ResultsIn tumors from ICI-DM patients, we did not find differences in expression of conventional type 1 diabetes autoantigens, but we did observe significant overexpression of ORM1, PLG, and G6PC, all of which have been implicated in type 1 diabetes or are related to pancreas and islet cell function. Interestingly, we observed a missense mutation in NLRC5 in tumors of 9 of the 13 ICI-DM patients that was not observed in the control patients treated with the same drugs for the same cancers. Germline DNA from the ICI-DM patients was sequenced; allNLRC5mutations were germline. The prevalence ofNLRC5germline variants was significantly greater than the general population (p=5.98×10−6). Although NLRC5 is implicated in development of type 1 diabetes, germlineNLRC5mutations were not found in public databases from patients with type 1 diabetes, suggesting a different mechanism of insulin-dependent diabetes in immunotherapy-treated patients with cancer.ConclusionsValidation of theNLRC5mutation as a potential predictive biomarker is warranted, as it might improve patient selection for treatment regimens. Furthermore, this genetic alteration suggests potential mechanisms of islet cell destruction in the setting of checkpoint inhibitor therapy.

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“…For example, T cells have been found in synovium during ICI‐induced arthritis 49,50 and the thyroid during ICI‐induced thyroiditis 51,52 . T cells have also been observed around the pancreatic islet patients with ICI‐induced diabetes 54,55 . Although suggestive that these T cells are contributing to the development of autoimmunity in irAEs, more work is needed in larger cohorts with longitudinal sampling and in‐depth phenotypic characterization to determine whether these are autoreactive T cells.…”

Section: Ici‐induced Iraesmentioning

confidence: 99%

“…51,52 T cells have also been observed around the pancreatic islet patients with ICI-induced diabetes. 54,55 Although suggestive that these T cells are contributing to the development of autoimmunity in irAEs, more work is needed in larger cohorts with longitudinal sampling and in-depth phenotypic characterization to determine whether these are autoreactive T cells. This work has already begun, but it is challenging given the relative rarity of ICI-induced autoimmunity, the continually changing landscape of ICI therapy with development of new drugs and expansion to new tumor types, and the range in the timing of irAE onset, which can occur soon after the start of ICI therapy but also after therapy has stopped.…”

Section: T-cell Signatures In Ici-induced Iraesmentioning

confidence: 99%

Immune‐related adverse events after immune check point inhibitors: Understanding the intersection with autoimmunity

Singh

Hocking

Buckner

2023

Immunological Reviews

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SummaryImmune checkpoint inhibitor therapies act through blockade of inhibitory molecules involved in the regulation of T cells, thus releasing tumor specific T cells to destroy their tumor targets. However, immune checkpoint inhibitors (ICI) can also lead to a breach in self‐tolerance resulting in immune‐related adverse events (irAEs) that include tissue‐specific autoimmunity. This review addresses the question of whether the mechanisms that drive ICI‐induced irAEs are shared or distinct with those driving spontaneous autoimmunity, focusing on ICI‐induced diabetes, ICI‐induced arthritis, and ICI‐induced thyroiditis due to the wealth of knowledge about the development of autoimmunity in type 1 diabetes, rheumatoid arthritis, and Hashimoto's thyroiditis. It reviews current knowledge about role of genetics and autoantibodies in the development of ICI‐induced irAEs and presents new studies utilizing single‐cell omics approaches to identify T‐cell signatures associated with ICI‐induced irAEs. Collectively, these studies indicate that there are similarities and differences between ICI‐induced irAEs and autoimmune disease and that studying them in parallel will provide important insight into the mechanisms critical for maintaining immune tolerance.

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Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor–induced diabetes

Cited by 24 publications

References 83 publications

Pancreatic Islet Cells Response to IFNγ Relies on Their Spatial Location within an Islet

Pancreatic Islet Cells Response to IFNγ Relies on Their Spatial Location within an Islet

Germline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors

Immune‐related adverse events after immune check point inhibitors: Understanding the intersection with autoimmunity

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