scRNAseq reveals T cell subsets responsible for ICI-induced colitis, twice!

Immunotherapy has fundamentally transformed cancer treatment by harnessing the body’s immune system to target and destroy cancer cells. Immune Checkpoint Inhibitors (ICIs) have recently emerged as a novel standard-of-care, constituting front-line therapies for several tumors. By blocking regulatory pathways that inhibit T-cell activity, ICIs like anti-PD-1 and anti-CTLA-4 antibodies have significantly improved survival rates in various cancers, including melanoma, lung cancer, and renal cell carcinoma. Many ICIs are also amongst the first tissue-agnostic therapies approved by the FDA, enabling their use in a broad clinical and therapeutic context. Nonetheless, despite their efficacy, ICIs come with a substantial risk of immune-related adverse events (irAEs), which can affect multiple organ systems.

As highlighted by two recent papers in Nature Medicine and Cancer Cell, gastrointestinal inflammation is the most common irAE (>60%) in patients taking checkpoint inhibitors. Some key findings from these studies include the identification of integrin-high CD8 T-cell subsets as key players in the process of checkpoint-blockade-related colitis, as well as the identification of IL-17, IL-23, and IL-26 as key players in this process. These findings nominate the use of biologics such as vedolizumab and ustekinumab to treat this adverse effect of ICIs. Furthermore, both studies identified recirculating CD8 T-cells as playing a role in this process, laying the groundwork for blood-based biomarker tests. Finally, a combination of PD-1 and CTLA-4 therapies was found to be potentially associated with a greater risk than anti-PD-1 monotherapy.?

To address these challenges, Scailyte is constructing a comprehensive data lake from ICI-treated patients. At Scailyte we believe that deciphering complex biological processes requires the high resolution of single-cell data. Therefore, our initiative, ScaiPod, aims to integrate multimodal data, including single-cell CITE-seq data and spatial transcriptomics, to identify biomarkers associated with both therapeutic response and adverse effects like checkpoint-blockade-related colitis, by leveraging Scailyte’s proprietary, unbiased biomarker discovery platform ScaiVision. By characterizing the molecular and cellular landscapes of irAEs, Scailyte seeks to identify early predictive markers that can signal higher risks for adverse events, thereby facilitating early intervention and personalized treatment adjustments.

This is expected to lead to a deeper understanding of the mechanisms of response, toxicity and resistance of checkpoint inhibitors, which can help guide drug developers and clinicians balance the positive effects of ICIs with their adverse outcomes.

Thomas, M.F., Slowikowski, K., Manakongtreecheep, K. et al. Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis. Nat Med 30, 1349–1362 (2024)

Gupta, T., Antanaviciute, A., Lee, C.H-J. et al. Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis. Cancer Cell 42, 797-814 (2024)