英国牛津大学Alison Simmons等研究人员合作在检查点诱发结肠炎患者体内追踪与检查点抑制剂结合的原位靶T细胞。该研究于2024年5月13日发表于国际一流学术期刊《癌细胞》。

研究人员利用多模态单细胞和亚细胞空间转录组学（ST）追踪了肠组织中与检查点抑制剂（CPI）结合的T细胞。在炎症组织中，靶点占据率增加，药物结合的T细胞位于不同的微域中，这些微域由特定的细胞间信号转导和转录梯度区分开来。CPI结合的细胞主要是CD4⁺ T细胞，包括CPI结合的外周辅助细胞、滤泡辅助细胞和调节性T细胞。

IFNγ CD8⁺ T细胞来自组织驻留记忆（TRM）和外周群体，显示出更受限制的靶占位特征，并与缺乏有效调控线索的受损上皮微域共定位。这些多模式分析确定了致病途径，并为新型预防策略提供了信息资源。

据介绍，CPI治疗癌症的成功受到了包括结肠炎在内的免疫相关不良反应的影响。CPI诱导的结肠炎以常驻粘膜IFNγ细胞毒性CD8⁺ T细胞的扩增为特征，但这些细胞是如何产生的还不清楚。

附：英文原文

Title: Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis

Author: Tarun Gupta, Agne Antanaviciute, Chloe Hyun-Jung Lee, Rosana Ottakandathil Babu, Anna Aulicino, Zoe Christoforidou, Paulina Siejka-Zielinska, Caitlin O’Brien-Ball, Hannah Chen, David Fawkner-Corbett, Ana Sousa Geros, Esther Bridges, Colleen McGregor, Nicole Cianci, Eve Fryer, Nasullah Khalid Alham, Marta Jagielowicz, Ana Mafalda Santos, Martin Fellermeyer, Simon J. Davis, Kaushal Parikh, Vincent Cheung, Lulia Al-Hillawi, Sarah Sasson, Stephanie Slevin, Oliver Brain, Elizabeth Bird-Lieberman, Simona Fourie, Richard Johnston, Heman Joshi, Debabrata Mujamdar, Simon Panter, Nishant Patodi, Sebastian Shaji, Jude Tidbury, Ajay Verma, Ricardo A. Fernandes, Hashem Koohy, Alison Simmons

Issue&Volume: 2024/05/13

Abstract: The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.

DOI: 10.1016/j.ccell.2024.04.010

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00134-X