Department of Pathology, Nanfang Hospital/School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, China; Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China.
Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen 518000, China.
Pharmacol Res. 2023 Nov;197:106974. doi: 10.1016/j.phrs.2023.106974. Epub 2023 Oct 28.
Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for patients with locally advanced rectal cancer (LARC). However, 20-40% of patients with LARC show little to no response to nCRT. Thus, comprehensively understanding the tumor microenvironment (TME), which might influence therapeutic efficacy, and identifying robust predictive biomarkers is urgently needed. Pre-treatment tumor biopsy specimens from patients with LARC were evaluated in detail through digital spatial profiling (DSP), public RNA sequencing datasets, and multiplex immunofluorescence (mIF). DSP analysis revealed distinct characteristics of the tumor stroma compared to the normal stroma and tumor compartments. We identified high levels of human leukocyte antigen-DR/major histocompatibility complex class II (HLA-DR/MHC-II) in the tumor compartment and B cells in the stroma as potential spatial predictors of nCRT efficacy in the Discovery cohort. Public datasets validated their predictive capacity for clinical outcomes. Using mIF in an independent nCRT cohort and/or the total cohort, we validated that a high density of HLA-DR/MHC-II+ cells in the tumor and CD20 + B cells in the stroma was associated with nCRT efficacy (all p ≤ 0.021). Spatial profiling successfully characterized the LARC TME and identified robust biomarkers with the potential to accurately predict nCRT response. These findings have important implications for individualized therapy.
新辅助放化疗（nCRT）已成为局部晚期直肠癌（LARC）患者的标准治疗方法。然而，20-40%的 LARC 患者对 nCRT 反应不佳或无反应。因此，全面了解可能影响治疗效果的肿瘤微环境（TME），并确定稳健的预测生物标志物是当务之急。通过数字空间分析（DSP）、公共 RNA 测序数据集和多重免疫荧光（mIF）对 LARC 患者的术前肿瘤活检标本进行了详细评估。DSP 分析显示，与正常基质和肿瘤区室相比，肿瘤基质具有明显的特征。我们发现肿瘤区室中人类白细胞抗原-DR/主要组织相容性复合体 II（HLA-DR/MHC-II）水平较高，基质中 B 细胞作为 nCRT 疗效的潜在空间预测因子在发现队列中。公共数据集验证了它们对临床结果的预测能力。使用 mIF 在独立的 nCRT 队列和/或总队列中，我们验证了肿瘤中 HLA-DR/MHC-II+细胞和基质中 CD20+B 细胞的高密度与 nCRT 疗效相关（均 p≤0.021）。空间分析成功地描述了 LARC 的 TME，并确定了具有准确预测 nCRT 反应潜力的稳健生物标志物。这些发现对个体化治疗具有重要意义。
