{
  "abstract": "Background While highly efficacious for numerous cancers, immune checkpoint inhibitors (ICIs) can cause unpredictable and potentially severe immune-related adverse events (irAEs), underscoring the need to understand irAE biology.Methods We used a multidimensional approach incorporating single-cell RNA sequencing, mass cytometry, multiplex cytokine assay, and antinuclear antibody (ANA) profiling to characterize the peripheral immune landscape of patients receiving ICI therapy according to irAE development.Results Analysis of 162 patients revealed that individuals who developed clinically significant irAEs exhibited a baseline proinflammatory, autoimmune-like state characterized by a significantly higher abundance of CD57 + T and natural killer (NK) T cells, plasmablasts, proliferating and activated CXCR3+ lymphocytes, CD8+ effector and terminal effector memory T cells, along with reduced NK cells and elevated plasma ANA levels. In irAE cases, we identified distinct baseline proinflammatory gene signatures, including markedly higher expression of IL1B and CXCL8 in monocytes and CXCR3, TNF, and IFNG in T/NK cells. TNF signaling was the most enriched pathway, while immunosuppressive genes SIGLEC7 and CXCR4 were downregulated. Following ICI initiation, these patients exhibited an enhanced shift toward an activated and inflammatory immune phenotype, including monocyte reprogramming characterized by upregulation of IL18 and elevated gene expression levels of CXCL10. Conversely, post-treatment levels of CXCL8 were decreased in irAE patients. Notably, in patients who did not develop clinically significant irAE, we identified increased baseline abundance of a TGFBIhigh myeloid cluster enriched in immunosuppressive markers such as STAB1. In addition, patients without irAE exhibited upregulation of TNF and AIRE, accompanied by distinct myeloid protumorigenic reprogramming.Conclusions A pre-existing activated, autoimmune-like proinflammatory state drives the development of irAE during ICI therapy through three key axes: increased plasmablast/ANA, heightened interferon-gamma/CXCL10/CXCR3 axis, and amplified TNF signaling. These findings may serve as potential peripheral immune biomarkers for predicting irAE and provide biological insights into the mechanisms governing and mitigating irAE.",
  "authors": [
    {
      "affiliations": [
        "Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Shaheen Khan"
    },
    {
      "affiliations": [
        "The University of Texas Southwestern Medical Center Medical School Lyda Hill Department of Bioinformatics, Dallas, Texas, USA",
        "Microsoft Corporation, Redmond, Washington, USA"
      ],
      "name": "Venkat S Malladi"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Mitchell S von Itzstein"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Hong Mu-Mosley"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Farjana J Fattah"
    },
    {
      "affiliations": [
        "Peter O'Donnell School of Public Health, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Yang Liu"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Mary E Gwin"
    },
    {
      "affiliations": [
        "Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Jason Y Park"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Suzanne M Cole"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Sheena Bhalla"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Jay Lohrey"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "David Hsiehchen"
    },
    {
      "affiliations": [
        "Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Angela Moses"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Peter O'Donnell School of Public Health, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Lyda Hill Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Tao Wang"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Yaming Xue"
    },
    {
      "affiliations": [
        "Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Angela B Mobley"
    },
    {
      "affiliations": [
        "Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "J David Farrar"
    },
    {
      "affiliations": [
        "Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "National Institutes of Health, Bethesda, Maryland, USA"
      ],
      "name": "Marjaan Imam"
    },
    {
      "affiliations": [
        "University of Missouri-Kansas City, Kansas City, Missouri, USA",
        "STARS Program, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Michelle Wu"
    },
    {
      "affiliations": [
        "Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Genecopoeia Inc, Rockville, Maryland, USA"
      ],
      "name": "Quan-Zhen Li"
    },
    {
      "affiliations": [
        "Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Edward K Wakeland"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Peter O'Donnell School of Public Health, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Lyda Hill Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Yang Xie"
    },
    {
      "affiliations": [
        "Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Jeffrey A SoRelle"
    },
    {
      "affiliations": [
        "Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Peter O'Donnell School of Public Health, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "David E Gerber"
    }
  ],
  "title": "Innate and adaptive immune features associated with immune-related adverse events",
  "uid": "ada745ee-4968-515d-b406-fe77890464b3"
}