Tumor immunogenomic features determine outcomes in metastatic colorectal cancer patients treated with standard-of-care combinations of bevacizumab and cetuximab

CALGB/SWOG 80405 was a randomized phase III trial in first-line mCRC patients treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on OS. Primary tumors (N=554) were profiled by RNAseq. Immune signatures of macrophages, lymphocytes, TGF-β, INF-γ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured. Increased M2 macrophage score (HR 6.30, 95% CI 3.0-12.15) and TGF-β signature expression (HR 1.35, 95% CI 1.05-1.77) were associated with shorter OS. Increased scores of plasma cells (HR 0.55, 95% CI 0.38-0.87) and activated memory CD4+ T cells (HR 0.34, 95% CI 0.16-0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0-1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8-47.8), to 31.0 (28.8-34.4), 25.2 (20.6-27.9), and 17.7 (13.5-20.4) months respectively (p-value 3.48e-11). New immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies. RNA-seq of 469 primary mCRC tumors, metastatic samples, or tumors of unknown origin

CALGB/SWOG 80405是一项针对一线转移性结直肠癌（mCRC）患者的随机Ⅲ期临床试验，受试患者分别接受贝伐珠单抗、西妥昔单抗、或二者联合化疗方案治疗。本研究旨在探讨肿瘤免疫特征对总生存期（OS）的影响。研究对554例原发肿瘤（N=554）进行了RNA测序（RNAseq），并检测了巨噬细胞、淋巴细胞、转化生长因子-β（TGF-β）、干扰素-γ（INF-γ）、伤口愈合及细胞毒性相关的免疫特征；同时通过CIBERSORTx算法测定了初始及记忆性B细胞、浆细胞、CD8+T细胞、静息与活化记忆性CD4+T细胞、M0及M2巨噬细胞、活化肥大细胞的浸润评分。分析结果显示，M2巨噬细胞浸润评分升高（风险比HR=6.30，95%置信区间CI：3.0~12.15）与TGF-β特征表达上调（HR=1.35，95%CI：1.05~1.77）均与更短的总生存期相关；而浆细胞评分升高（HR=0.55，95%CI：0.38~0.87）与活化记忆性CD4+T细胞评分升高（HR=0.34，95%CI：0.16~0.65）则与更长的总生存期相关。基于上述四项免疫特征的最优截断值，本研究将患者分为携带4项、3项、2项、0~1项与更长总生存期相关的有益特征的亚组，其对应的中位总生存期（95%CI）分别为42.5（35.8~47.8）个月、31.0（28.8~34.4）个月、25.2（20.6~27.9）个月及17.7（13.5~20.4）个月（p值=3.48×10^-11）。新型免疫特征可被进一步评估以优化患者治疗响应，该研究结果也为开发更有效的免疫治疗策略提供了理论依据。本数据集包含469例原发转移性结直肠癌肿瘤、转移样本或来源不明肿瘤的RNA测序数据。