Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Department of Dermatology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Nat Commun. 2021 Nov 18;12(1):6726. doi: 10.1038/s41467-021-26974-6.
Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. While a subset of patients derive benefit from PD-1 blockade, there is a critically unmet need for predictive biomarkers of response. Herein, we perform CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced CTCL patients enrolled in a pembrolizumab clinical trial (NCT02243579). We find no differences in the frequencies of immune or tumor cells between responders and non-responders. Instead, we identify topographical differences between effector PD-1 CD4 T cells, tumor cells, and immunosuppressive Tregs, from which we derive a spatial biomarker, termed the SpatialScore, that correlates strongly with pembrolizumab response in CTCL. The SpatialScore coincides with differences in the functional immune state of the tumor microenvironment, T cell function, and tumor cell-specific chemokine recruitment and is validated using a simplified, clinically accessible tissue imaging platform. Collectively, these results provide a paradigm for investigating the spatial balance of effector and suppressive T cell activity and broadly leveraging this biomarker approach to inform the clinical use of immunotherapies.
皮肤 T 细胞淋巴瘤（CTCL）是一种罕见但侵袭性很强的癌症，目前尚无有效的治疗方法。虽然有一部分患者从 PD-1 阻断治疗中获益，但对于预测反应的生物标志物存在着迫切的需求。在此，我们对 14 名接受 pembrolizumab 临床试验（NCT02243579）的晚期 CTCL 患者的 70 个肿瘤区域进行了 CODEX 多重组织成像和 RNA 测序。我们没有发现应答者和无应答者之间免疫细胞或肿瘤细胞的频率有差异。相反，我们在效应 PD-1 CD4 T 细胞、肿瘤细胞和免疫抑制性 Tregs 之间发现了拓扑差异，由此我们得出了一个空间生物标志物，称为 SpatialScore，它与 CTCL 中 pembrolizumab 的应答强烈相关。SpatialScore 与肿瘤微环境中免疫功能状态、T 细胞功能以及肿瘤细胞特异性趋化因子募集的差异一致，并通过简化的、临床上可及的组织成像平台进行了验证。总的来说，这些结果为研究效应和抑制性 T 细胞活性的空间平衡提供了范例，并广泛利用这种生物标志物方法为免疫治疗的临床应用提供信息。
