原创 陈欣 华西医院耳鼻喉科

华西耳鼻喉前沿学术速递——文献导读（第69期）

【Nature Cancer】2025年2月-2025年3月刊论文导读

期刊介绍：

Nature Cancer作为《自然》系列子刊，填补了癌症研究领域缺乏多学科融合期刊的空白，整合生命科学、物理科学、应用科学及社会科学的研究成果，促进跨领域协作‌，2024年影响因子为23.5，稳居医学/肿瘤学领域顶级期刊之列‌。

Volume 6 Issue 2, February 2025

2025年2-3月一共发表5篇文章，其中Articles 4篇，Brief Communication 1篇。

1. Microbiome dysbiosis, neutrophil recruitment and mesenchymal transition of mesothelial cells promotes peritoneal metastasis of colorectal cancer

微生物组菌群失调、中性粒细胞募集和间皮细胞间充质转化促进结直肠癌腹膜转移

复旦大学附属肿瘤医院大肠外科、复旦大学上海医学院肿瘤学系、北京大学生命科学学院清华大学生命科学中心（CLS）生物医药创新中心、美国加利福尼亚州蒙罗维亚市希望之城贝克曼研究所生物医学研究中心分子诊断学和实验治疗学系、美国加利福尼亚州杜阿尔特市希望之城综合癌症中心

Summary

Peritoneal metastasis (PM) is common in colorectal cancer (CRC), yet its underlying mechanisms are poorly understood. Here, we explored the transcriptional profile of CRC, PM and adjacent tissues revealing key players that facilitate PM. Single-cell analysis of 48 matched samples from 12 patients revealed that remodeling of malignant cells and the tumor microenvironment promotes CRC progression and metastasis. Multiplexed imaging confirmed depletion in PM by enrichment in CRC tissues of neutrophils associated with mucosal immunity disruption, intestinal microbiota dysbiosis and mesenchymal transition of both cancerous and mesothelial cells. Functional analyses in cell lines, organoids and in vivo models demonstrated that dysbiosis promoted inflammation and protumor neutrophil recruitment, while coupled mesenchymal transition of malignant and mesothelial cells disrupted the stromal structure and increased cancer cell invasiveness. Our findings suggest that targeting mesothelial cells and tumor microenvironment remodeling may offer therapeutic strategies for CRC-PM.

摘要

腹膜转移（PM）在结直肠癌（CRC）中很常见，但其潜在机制尚不清楚。研究团队通过分析CRC、PM及其相邻组织的转录谱，揭示了促进PM的关键机制。对12名患者的48个匹配样本进行单细胞分析显示，恶性细胞和肿瘤微环境的重塑促进了CRC的进展和转移。多重成像技术显示，PM中中性粒细胞在CRC组织中富集，与粘膜免疫破坏、肠道菌群失调及癌细胞和间皮细胞的间质转化相关。在细胞系、类器官和小鼠模型中的功能分析表明，微生物群失调促进了炎症和促肿瘤中性粒细胞的招募，而恶性肿瘤细胞和间皮细胞的联合间质转化破坏了基质结构并增加了癌细胞的侵袭性。研究结果表明，靶向间皮细胞和肿瘤微环境重塑可能是结直肠癌腹膜转移（CRC-PM）的治疗策略。

Atezolizumab following definitive chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma – a multicenter phase 2 trial (EPOC1802)

不可切除的局部晚期食管鳞状细胞癌患者在根治性放化疗后使用阿替利珠单抗——一项多中心2期试验（EPOC1802）

日本柏市国立癌症中心东医院胃肠病学和胃肠道肿瘤科

Summary

Platinum-based definitive chemoradiotherapy (dCRT) is the standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) that invades the aorta, vertebral body or trachea; however, complete response rates remain low (11–25%), leading to poor survival. To evaluate the additive efficacy of the anti-PD-L1 antibody drug atezolizumab, we conducted a phase 2, multicenter, single-arm trial of 1 year of atezolizumab treatment following dCRT in 40 patients with unresectable locally advanced ESCC recruited from seven Japanese centers (UMIN000034373). The confirmed complete response (cCR) rate (primary end point) of the first consecutive 38 patients was 42.1% (90% CI 28.5–56.7%). Regarding the secondary end points, the median progression-free survival and 12-month progression-free survival rates of all 40 patients were 3.2 months and 29.6%, respectively, and the preliminary median overall survival with short-term follow-up and 12-month overall survival rate were 31.0 months and 65.8%, respectively. Other secondary end points evaluated included the cCR rate determined by an investigator’s assessment in the locoregionally recurrent ESCC cohort, cCR rate determined by central assessment, overall response rate and incidence of adverse events. No treatment-related death occurred during the study. Atezolizumab monotherapy after dCRT resulted in a promising cCR rate, although long-term survival data are required.

摘要

基于铂类的确定性放化疗（dCRT）是侵犯主动脉、椎体或气管的不可切除局部晚期食管鳞状细胞癌（ESCC）患者的标准治疗方法；然而，完全缓解率仍然较低（11-25%），导致生存预后较差。为了评估抗PD-L1抗体药物阿替利珠单抗的附加疗效，研究团队进行了一项2期多中心单臂试验，来自七个日本中心（UMIN000034373）的40名不可切除局部晚期ESCC患者在dCRT后接受1年的阿替利珠单抗治疗。结果发现，首批连续38名患者的确认完全缓解率（cCR）（主要终点）为42.1%（90% CI 28.5-56.7%）。在次要终点方面，所有40名患者的中位无进展生存期和12个月无进展生存率分别为3.2个月和29.6%；短期随访的初步中位总生存期和12个月总生存率分别为31.0个月和65.8%。评估的其他次要终点包括由研究者评估确定的局部区域复发ESCC队列的cCR率、中心评估确定的cCR率、总缓解率和不良事件发生率。研究期间未发生与治疗相关的死亡事件。综上可知，尽管还需要累积长期生存数据，在dCRT后的阿替利珠单抗单药治疗显示出有前景的完全缓解率。

3. Pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient advanced solid tumors: updated results of the KEYNOTE-158 trial

帕博利珠单抗治疗微卫星不稳定性高和错配修复缺陷型晚期实体瘤：KEYNOTE-158试验的最新结果

美国俄亥俄州立大学哥伦布市俄亥俄州立大学韦克斯纳医学中心

Summary

The phase 2 trial KEYNOTE-158 (NCT02628067) evaluated pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient (MSI-H/dMMR) noncolorectal tumors. With 373 participants (95% with baseline MSI/dMMR documentation) and 4.5 years of follow-up, the primary endpoint of overall response rate was 33.8%. Secondary endpoints of duration of response, overall survival and progression-free survival were 63.2, 19.8 and 4.0 months, respectively. Grade ≥3 treatment-related adverse events occurred in 50 (13%) participants. These results further support pembrolizumab use in MSI-H/dMMR tumors.

摘要

2期试验KEYNOTE-158（NCT02628067）评估了帕博利珠单抗在微卫星不稳定性高和错配修复缺陷（MSI-H/dMMR）的非结直肠肿瘤中的应用。在373名参与者（95%有基线MSI/dMMR记录）和4.5年的随访中，主要终点总反应率为33.8%。次要终点反应持续时间、总生存期和无进展生存期分别为63.2个月、19.8个月和4.0个月。50人（13%）发生了≥3级治疗相关不良事件。这些结果进一步支持了帕博利珠单抗在MSI-H/dMMR肿瘤中的应用。

4. An antibody–toxin conjugate targeting CD47 linked to the bacterial toxin listeriolysin O for cancer immunotherapy

一种与细菌毒素李斯特菌溶血素O相连、靶向CD47的抗体-毒素偶联物，用于癌症免疫治疗

美国德克萨斯州休斯顿德克萨斯大学 MD 安德森癌症中心放射肿瘤学系

Summary

Antigen-presenting cells phagocytose tumor cells and subsequently cross-present tumor-derived antigens. However, these processes are impeded by phagocytosis checkpoints and inefficient cytosolic transport of antigenic peptides from phagolysosomes. Here, using a microbial-inspired strategy, we engineered an antibody–toxin conjugate (ATC) that targets the ‘don’t eat me’ signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47–LLO). CD47–LLO promotes cancer cell phagocytosis by macrophages followed by LLO release and activation to form pores on phagolysosomal membranes that enhance antigen cross-presentation of tumor-derived peptides and activate cytosolic immune sensors. CD47–LLO treatment in vivo significantly inhibited the growth of both localized and metastatic breast and melanoma tumors and improved animal survival as a monotherapy or in combination with checkpoint blockade. Together, these results demonstrate that designing ATCs to promote immune recognition of tumor cells represents a promising therapeutic strategy for treating multiple cancers.

摘要

抗原呈递细胞吞噬肿瘤细胞，随后交叉呈递肿瘤衍生抗原。然而，吞噬检查点和吞噬溶酶体抗原肽的低效胞浆转运阻碍了这些过程。该研究团队采用一种受微生物启发的策略，设计了一种抗体-毒素共轭物（ATC），它以 “别吃我 ”信号CD47为靶标，通过可裂解连接体（CD47-LLO）与来自细胞内单核细胞增生李斯特菌的细菌毒素李斯特溶菌素O相连。CD47–LLO可促进巨噬细胞吞噬癌细胞，随后释放并激活LLO，在吞噬溶酶体膜上形成孔，从而增强肿瘤肽的抗原交叉呈递，并激活细胞免疫传感器。作为一种单一疗法或与检查点阻断疗法联合使用，体内 CD47-LLO 治疗可显著抑制局部和转移性乳腺癌和黑色素瘤的生长，并提高动物的存活率。以上结果共同表明，设计ATC来促进肿瘤细胞的免疫识别，是治疗多种癌症的一种很有前景的治疗策略。

5. Neoadjuvant cabozantinib for locally advanced nonmetastatic clear cell renal cell carcinoma: a phase 2 trial

新辅助卡博替尼治疗局部晚期非转移性透明细胞肾细胞癌：一项2期试验

美国佐治亚州亚特兰大市埃默里大学 Winship 癌症研究所

Summary

Cabozantinib is an oral multikinase inhibitor approved for treatment in metastatic renal cell carcinoma (RCC). We conducted a phase 2, nonrandomized, single-arm clinical trial (NCT04022343) of cabozantinib treatment for 12 weeks in 17 patients with locally advanced, biopsy-proven, nonmetastatic clear cell RCC before surgical resection. The primary end point was the objective response rate (complete and partial responses) at week 12 and secondary end points included safety, tolerability, clinical and surgical outcomes, and quality of life. Six patients (35%) experienced a partial response and 11 patients (65%) had stable disease. The most common adverse events were diarrhea (n = 12, 70.6%), anorexia, fatigue and hypertension (n = 10, 58.8%), nausea and palmar-plantar erythrodysesthesia syndrome (n = 9, 52.9%). No treatment grade 4 or 5 adverse events related to cabozantinib or surgery occurred. The 1-year disease-free survival and overall survival were 82.4% (95% CI 54.7–93.9%) and 94.1% (95% CI 65–99.1%), respectively. Cabozantinib treatment activated CD8 T cells in the blood, depleted myeloid populations and induced immune niches for TCF1 stem-like CD8 T cells. Cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced nonmetastatic clear cell RCC.

摘要

卡博替尼是一种口服多激酶抑制剂，已被批准用于治疗转移性肾细胞癌（RCC）。该研究团队开展了一项2期非随机单臂临床试验（NCT04022343），对17例手术切除前局部晚期、活检证实的非转移性透明细胞RCC患者进行了为期12周的卡博替尼治疗。主要终点是第12周时的客观反应率（完全和部分反应），次要终点包括安全性、耐受性、临床和手术效果以及生活质量。6名患者（35%）出现部分应答，11名患者（65%）病情稳定。最常见的不良反应为腹泻（12例，70.6%）、厌食、乏力和高血压（10例，58.8%）、恶心和掌跖红斑综合征（9例，52.9%）。没有发生与卡博替尼或手术相关的4级或5级不良反应。1年无病生存率和总生存率分别为82.4%（95% CI 54.7-93.9%）和94.1%（95% CI 65-99.1%）。卡博替尼治疗激活了血液中的CD8 T细胞，耗尽了髓系细胞群，并诱导了TCF1干样CD8 T细胞的免疫龛。卡博替尼对局部晚期非转移性透明细胞RCC患者的新辅助治疗具有临床活性和安全性。

汇报人：陈欣

导师：任建君

审核：张宇阳、胥飞宇、任建君