全面的瘤内免疫定量分析及免疫评分对生存的重大影响。

Comprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival.

机构信息

Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France; Inovarion, Paris, France; Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium; Department of Immunology, HEGP, Assistance Publique-Hopitaux de Paris, Paris, France; AstraZeneca, Cambridge, UK; Departments of General and Digestive Surgery, HEGP, AP-HP, Assistance Publique-Hopitaux de Paris, Paris, France; Grand Hopital de Charleroi, Charleroi, Belgium.

出版信息

J Natl Cancer Inst. 2018 Jan 1;110(1). doi: 10.1093/jnci/djx123.

DOI:10.1093/jnci/djx123

PMID:28922789

Abstract

BACKGROUND

This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients.

METHODS

Complete curative resection of metastases (n = 441) was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient's disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided.

RESULTS

The spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3-4: DFS rate = 27.9%, 95% CI = 15.2 to 51.3; vs I 0-1-2: DFS rate = 12.3%, 95% CI = 4.9 to 30.6; HR = 0.45, 95% CI = 0.28 to 0.70, P = .02; I 3-4: OS rate = 64.6%, 95% CI = 46.6 to 89.6; vs I 0-1-2: OS rate = 32.5%, 95% CI = 17.2 to 61.4; HR = 0.32, 95% CI = 0.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3-4: DFS rate = 25.7%, 95% CI = 14.2 to 46.6; vs TB 0-1-2: DFS rate = 5.0%, 95% CI = 0.8 to 32.4; HR = 0.36, 95% CI = 0.22 to 0.57, P < .001; TB 3-4: OS rate = 63.7%, 95% CI = 46.4 to 87.5; vs TB 0-1-2: OS rate: 21.4%, 95% CI = 9.2 to 49.8; HR = 0.25, 95% CI = 0.12 to 0.51, P < .001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5 months, while low patients survived only 25.1 to 38.3 months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HR = 0.28, 95% CI = 0.15 to 0.52, P = .001) and OS (HR = 0.25, 95% CI = 0.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P < .001), while response to treatment was not.

CONCLUSIONS

Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.

摘要

背景

本研究评估了转移性免疫景观如何影响结直肠癌（CRC）患者的治疗反应和预后。

方法

对两个患者队列（n=153）的转移灶进行了完全治愈性切除（n=441）。在所有转移灶的中心和侵袭边缘定量评估免疫密度。在多变量 Cox 比例风险模型中，分析免疫评分和 T、B 细胞（TB）评分与影像学和病理学反应以及患者的无病生存（DFS）和总生存（OS）之间的关系。所有统计检验均为双侧检验。

结果

转移灶内免疫细胞的空间分布不均匀。患者以及同一患者的转移灶具有不同的免疫浸润和对治疗的反应。治疗获益与免疫密度增加呈统计学显著相关。在所有转移灶中，在免疫浸润最少的转移灶中评估的免疫评分（I）和 TB 评分是 DFS 和 OS 的最强预测因素（五年随访，免疫评分：I3-4：DFS 率=27.9%，95%CI=15.2 至 51.3；I0-1-2：DFS 率=12.3%，95%CI=4.9 至 30.6；HR=0.45，95%CI=0.28 至 0.70，P=0.02；I3-4：OS 率=64.6%，95%CI=46.6 至 89.6；I0-1-2：OS 率=32.5%，95%CI=17.2 至 61.4；HR=0.32，95%CI=0.15 至 0.66，P=0.001，C 指数=65.9%；五年随访，TB 评分：TB3-4：DFS 率=25.7%，95%CI=14.2 至 46.6；TB0-1-2：DFS 率=5.0%，95%CI=0.8 至 32.4；HR=0.36，95%CI=0.22 至 0.57，P<0.001；TB3-4：OS 率=63.7%，95%CI=46.4 至 87.5；TB0-1-2：OS 率=21.4%，95%CI=9.2 至 49.8；HR=0.25，95%CI=0.12 至 0.51，P<0.001，C 指数=67.8%）。高 TB 评分和免疫评分患者的中位生存时间为 70.5 个月，而低评分患者的生存时间仅为 25.1 至 38.3 个月。高免疫浸润的无反应患者的 DFS（HR=0.28，95%CI=0.15 至 0.52，P=0.001）和 OS（HR=0.25，95%CI=0.1 至 0.62，P=0.001）得到延长。在多变量分析中，免疫参数仍然是与 DFS 和 OS 相关的唯一具有统计学意义的预后因素（P<0.001），而治疗反应则不是。