Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer.
Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer.
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DOI：
10.1158/2767-9764.crc-23-0550
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发表时间：
2024-01-25
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Sotigalimab是一种激动性抗CD 40 mAb，可调节抗肿瘤免疫应答。在局部晚期食管/胃食管连接部（E/GEJ）癌患者中进行的一项sotigalimab联合新辅助放化疗（CRT）的II期临床试验中，主要结局为疗效（通过病理学完全缓解（pCR）率测量），该联合治疗在38%的治疗患者中诱导了pCR。我们在本临床试验获得的样本中研究了sotigalimab的作用机制。在基线、初始剂量的sotigalimab后和CRT完成后手术时，从6名患者中采集肿瘤活检和外周血样本。使用高维单细胞技术，包括组合的单细胞RNA测序和蛋白质组学（CITEseq）和多重离子束成像，来分析免疫应答。Sotigalimab显著重塑了外周和肿瘤微环境（TME）内的免疫区室，增加了与抗原加工和呈递相关的分子的表达，并改变了骨髓细胞中的代谢途径。伴随着骨髓细胞中的这些变化，sotigalimab治疗引发了新的T细胞克隆型，并增加了T细胞的密度和活化，细胞毒性功能增强。Sotigalimab给药还诱导TME中的Tclad频率降低。这些发现表明，单剂量的sotigalimab导致增强的抗原呈递，可以激活T细胞并诱导新的T细胞克隆。TME的这种重组提供了对有效的抗肿瘤免疫应答的发展和改善的临床结果至关重要的元素。
Sotigalimab is an agonistic anti-CD40 mAb that can modulate antitumor immune responses. In a phase II clinical trial of sotigalimab combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction (E/GEJ) cancer with the primary outcome of efficacy as measured by pathologic complete response (pCR) rate, the combination induced pCR in 38% of treated patients. We investigated the mechanism of action of sotigalimab in samples obtained from this clinical trial. Tumor biopsies and peripheral blood samples were collected at baseline, following an initial dose of sotigalimab, and at the time of surgery after CRT completion from six patients. High dimensional single-cell techniques were used, including combined single-cell RNA-sequencing and proteomics (CITEseq) and multiplexed ion beam imaging, to analyze immune responses. Sotigalimab dramatically remodeled the immune compartment in the periphery and within the tumor microenvironment (TME), increasing expression of molecules related to antigen processing and presentation and altering metabolic pathways in myeloid cells. Concomitant with these changes in myeloid cells, sotigalimab treatment primed new T cell clonotypes and increased the density and activation of T cells with enhanced cytotoxic function. Sotigalimab treatment also induced a decrease in the frequency of Tregs in the TME. These findings indicate that a single dose of sotigalimab leads to enhanced antigen presentation that can activate T cells and induce new T cell clones. This restructuring of the TME provides elements which are critical to the development of effective antitumor immune responses and improved clinical outcomes.