Innate and Adaptive Immune Features Associated With Immune-Related Adverse Events

Authors

Shaheen Khan
Venkat S Malladi
Mitchell S von Itzstein
Hong Mu-Mosley
Farjana J Fattah
Yang Liu
Mary E Gwin
Jason Y Park
Suzanne M Cole
Sheena Bhalla
Jay Lohrey
David Hsiehchen
Angela Moses
Tao Wang
Yaming Xue
Angela B Mobley
J David Farrar
Marjaan Imam
Michelle Wu
Quan-Zhen Li
Edward K Wakeland
Yang Xie
Jeffrey A SoRelle
David E Gerber

Publication Date

9-10-2025

Journal

The Journal for ImmunoTherapy of Cancer

DOI

10.1136/jitc-2025-012414

PMID

40930749

PMCID

PMC12506470

PubMedCentral® Posted Date

9-10-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Immunity, Innate, Adaptive Immunity, Male, Female, Middle Aged, Neoplasms, Immune Checkpoint Inhibitors, Aged, Immune related adverse event - irAE, Immunotherapy, Immune Checkpoint Inhibitor, Autoimmune, Antibody

Published Open-Access

yes

Recommended Citation

Khan, Shaheen; Malladi, Venkat S; von Itzstein, Mitchell S; et al., "Innate and Adaptive Immune Features Associated With Immune-Related Adverse Events" (2025). Faculty, Staff and Student Publications. 6201.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6201