2. Academic Validation
  3. Polyfunctional IL-21+ IFNG+ T follicular helper cells contribute to checkpoint inhibitor diabetes mellitus and can be targeted by JAK inhibitor therapy

Polyfunctional IL-21+ IFNG+ T follicular helper cells contribute to checkpoint inhibitor diabetes mellitus and can be targeted by JAK inhibitor therapy

  • bioRxiv. 2024 Dec 3:2024.11.27.625710. doi: 10.1101/2024.11.27.625710.
Nicole Huang 1,  Jessica Ortega 2,  Kyleigh Kimbrell 1,  Joah Lee 1,  Lauren N Scott 3,  Esther M Peluso 4,  Sarah J Wang 1,  Ellie Kao 5,  Kristy Kim 1,  Jarod Olay 6,  Zoe Quandt 7,  Trevor E Angell 8,  Maureen A Su 6 9,  Melissa G Lechner 1
Affiliations

Affiliations

  • 1 Division of Endocrinology, Diabetes, and Metabolism, University of California Los Angeles (UCLA) David Geffen School of Medicine, Los Angeles, CA 90095.
  • 2 UCSF Medical School, San Francisco, CA 94143.
  • 3 University of Kansas Medical School, Kansas City, KS 66160.
  • 4 UCLA/California Institute of Technology Medical Scientist Training Program, UCLA David Geffen School of Medicine, Los Angeles, CA 90095.
  • 5 California State Polytechnic University, Pomona, CA 91768.
  • 6 Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095.
  • 7 Division of Endocrinology and Metabolism, University of California San Francisco Medical School, San Francisco, CA 94143.
  • 8 Division of Endocrinology and Diabetes, University of Southern California Keck School of Medicine; Los Angeles, CA 90033.
  • 9 Division of Pediatric Endocrinology, UCLA David Geffen School of Medicine; Los Angeles, CA 90095.
PMID: 39677814 DOI: 10.1101/2024.11.27.625710
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 beta-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. Here, we identify expansion CD4+ T follicular helper (Tfh) cells expressing interleukin 21 (IL-21) and interferon gamma (IFNG) as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFNG are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFNG 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.

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