Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy
Nicole L. Huang, Jessica G. Ortega, Kyleigh Kimbrell, Joah Lee, Lauren N. Scott, Esther M. Peluso, Sarah J. Wang, Ellie Y. Kao, Kristy Kim, Jarod Olay, Jaden N. Nguyen, Zoe Quandt, Trevor E. Angell, Maureen A. Su, Melissa G. Lechner
Nicole L. Huang, Jessica G. Ortega, Kyleigh Kimbrell, Joah Lee, Lauren N. Scott, Esther M. Peluso, Sarah J. Wang, Ellie Y. Kao, Kristy Kim, Jarod Olay, Jaden N. Nguyen, Zoe Quandt, Trevor E. Angell, Maureen A. Su, Melissa G. Lechner
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Research Article Oncology

Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy

Abstract

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption, and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic β-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8+ T cells, the role for CD4+ T cells in ICI-T1DM is less understood. We identify expansion of CD4+ T follicular helper (Tfh) cells expressing IL-21 and IFN-γ as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFN-γ are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFN-γ both signal through JAK/STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+ Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.

Authors

Nicole L. Huang, Jessica G. Ortega, Kyleigh Kimbrell, Joah Lee, Lauren N. Scott, Esther M. Peluso, Sarah J. Wang, Ellie Y. Kao, Kristy Kim, Jarod Olay, Jaden N. Nguyen, Zoe Quandt, Trevor E. Angell, Maureen A. Su, Melissa G. Lechner

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Figure 3

JAKi ruxolitinib provides robust protection against ICI autoimmune DM.

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JAKi ruxolitinib provides robust protection against ICI autoimmune DM. (...
(A) Proposed JAK signaling inhibition downstream from IL-21 and IFN-γ to halt autoimmune response. (B) Schematic for treatment of mice with JAKi ruxolitinib (left) and incidence of autoimmune DM (right) in NOD mice treated with anti–PD-1 immunotherapy or Iso, and ruxolitinib or control food gel. Iso (6 males, 13 females); Iso + Ruxo (3 males, 3 females); anti–PD-1 + Ruxo (6 males, 8 females); anti–PD-1 (8 males, 18 females). (C) Representative H&E-stained pancreas histology sections of anti–PD-1 or Iso-treated NOD mice (original magnification, 100×) fed ruxolitinib or control food. Arrow indicates an islet of Langerhans. (D) Insulitis index of anti–PD-1 or Iso-treated NOD mice given ruxolitinib (Iso: 1 males, 1 females; anti–PD-1: 4 males, 4 females); ^data for anti–PD-1 mice given control chow are the same as shown in Figure 2E, reshown here for comparative purposes. (E) Schematic and absolute cell counts of pancreatic islet–infiltrating CD45+ cells, as determined by flow cytometry, across Iso + vehicle (n = 12), anti–PD-1 + vehicle (n = 15), and anti–PD-1 + ruxolitinib (n = 5) conditions. Each point represents data from 1 animal. (F) Representative multi-immunofluorescence staining and microscopy images (original magnification, 40×) of CD4, CD8, B220, and DAPI in the islet of Langerhans across experimental conditions. Arrow indicates islet in merge images. (G) Quantification of CD4+ T cell, CD8+ T cell, and B220+ B cell counts per pancreatic islet of indicated treatment condition by immunofluorescence from mice treated with Ruxo + anti–PD-1 (3 males, 2 females); data for Iso or anti–PD-1 treated mice given control chow are the same as shown in Figure 2F, reshown here for comparative purposes. Data are presented as mean ± SD (E and G). Comparisons by log-rank test (B), Fisher’s exact test (D), or ANOVA with Welch’s correction and pairwise comparison by Tukey’s test (E and G). **P < 0.01, ****P < 0.0001.