418P - Decoding the intricate cellular makeup of immune-related adverse events using single-cell and spatial analysis

Background

The clinical efficacy of immune-checkpoint inhibitors is complicated by the risk for immune-related adverse events (irAEs) that can involve any organ systems. Among the most frequently observed irAEs are gastrointestinal and respiratory complications, which can significantly impact patients' quality of life and treatment outcomes. Understanding the underlying cellular mechanisms and immune landscape associated with irAEs is crucial for optimizing patient management and developing targeted interventions.

Methods

This pilot trial was conducted as part of a prospective multicentre cohort study (NCT04631731). Visium spatial transcriptomic profiling was performed on n=4 baseline FFPE mesothelioma tissues and Chromium 3’ single-cell sequencing of n=16 matched peripheral blood mononuclear cells (PBMCs) prior to treatment and following the initiation of therapy (+/- irAEs). All samples were obtained from patients treated with Ipilimumab (1 mg/kg) + Nivolumab (3 mg/kg).

Results

To determine the location of tumour-infiltrating T cells within spatially profiled tissues we utilized an ImSig. Tumour tissue from two patients that developed immune-related pneumonitis possessed a greater number of T cell assigned spots compared to the two patients without irAEs: n=250 and n=137 respectively. Differential gene expression analysis identified n=122 dysregulated genes in tumour-infiltrating T cells corresponding to biological processes that have the potential to contribute to immunotherapy response. Further single-cell sequencing of PBMCs derived from patients with immunotherapy-related colitis identified distinct populations and transcriptional profiles associated with the development of colitis. These findings have shed light on the dysregulated immune responses and potential immune cell interactions underlying irAEs, providing valuable insights into the pathogenesis of ICI toxicity.

Conclusions

This pilot analysis provides valuable insights into the multi-omic signatures associated with the irAEs. The ongoing recruitment in NCT04631731 holds promise for successful validation of preliminary data thus providing new perspectives on establishing biomarkers of immunotherapy toxicity in the near future.

Clinical trial identification

NCT04631731.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bristol Myers Squibb.

Disclosure

All authors have declared no conflicts of interest.