DataSheet_2_CD8+ T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types.pdf

BackgroundCancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are critical for immune suppression by restricting immune cell infiltration in the tumor stromal zones from penetrating tumor islands and changing their function status, particularly for CD8+ T cells. However, assessing and quantifying the impact of CAFs on immune cells and investigating how this impact is related to clinical outcomes, especially the efficacy of immunotherapy, remain unclear.
Materials and methodsThe TME was characterized using immunohistochemical (IHC) analysis using a large-scale sample size of gene expression profiles. The CD8+ T cell/CAF ratio (CFR) association with survival was investigated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) lung cancer cohorts. The correlation between CFR and immunotherapeutic efficacy was computed in five independent cohorts. The correlation between CFR and objective response rates (ORRs) following pembrolizumab monotherapy was investigated in 20 solid tumor types. To facilitate clinical translation, the IHC-detected CD8/α-SMA ratio was applied as an immunotherapeutic predictive biomarker in a real-world lung cancer cohort.
ResultsCompared with normal tissue, CAFs were enriched in cancer tissue, and the amount of CAFs was overwhelmingly higher than that in other immune cells. CAFs are positively correlated with the extent of immune infiltration. A higher CFR was strongly associated with improved survival in lung cancer, melanoma, and urothelial cancer immunotherapy cohorts. Within most cohorts, there was no clear evidence for an association between CFR and programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB). Compared with TMB and PD-L1, a higher correlation coefficient was observed between CFR and the ORR following pembrolizumab monotherapy in 20 solid tumor types (Spearman’s r = 0.69 vs. 0.44 and 0.21). In a real-world cohort, patients with a high CFR detected by IHC benefited considerably from immunotherapy as compared with those with a low CFR (hazard ratio, 0.37; 95% confidence interval, 0.19–0.75; p < 0.001).
ConclusionsCFR is a newly found and simple parameter that can be used for identifying patients unlikely to benefit from immunotherapy. Future studies are needed to confirm this finding.

研究背景：肿瘤微环境（tumor microenvironment, TME）内的肿瘤相关成纤维细胞（Cancer-associated fibroblasts, CAFs）可通过限制免疫细胞浸润肿瘤间质区并穿透肿瘤岛，以及改变免疫细胞的功能状态，发挥免疫抑制作用，尤其对CD8+ T细胞影响显著。然而，当前对肿瘤相关成纤维细胞对免疫细胞的影响进行评估与量化，以及阐明该影响与临床结局（尤其是免疫治疗疗效）之间的关联仍不明确。
材料与方法：本研究通过免疫组化（immunohistochemical, IHC）分析，并结合大样本量的基因表达谱数据对肿瘤微环境进行表征。在癌症基因组图谱（The Cancer Genome Atlas, TCGA）与基因表达综合数据库（Gene Expression Omnibus, GEO）的肺癌队列中，分析了CD8+ T细胞/肿瘤相关成纤维细胞比值（CD8+ T cell/CAF ratio, CFR）与患者生存的关联；在5个独立队列中计算了CFR与免疫治疗疗效的相关性；在20种实体瘤类型中，分析了帕博利珠单抗单药治疗后CFR与客观缓解率（objective response rates, ORRs）的相关性。为推动临床转化，本研究将免疫组化检测得到的CD8/α平滑肌肌动蛋白（α-smooth muscle actin, α-SMA）比值作为免疫治疗预测生物标志物，在真实世界肺癌队列中进行了验证。
研究结果：与正常组织相比，肿瘤组织中肿瘤相关成纤维细胞富集，且其数量显著高于其他免疫细胞；肿瘤相关成纤维细胞与免疫浸润程度呈正相关。在肺癌、黑色素瘤及尿路上皮癌的免疫治疗队列中，较高的CFR与更好的患者生存显著相关。在大多数队列中，未发现CFR与程序性死亡受体配体1（programmed death-ligand 1, PD-L1）或肿瘤突变负荷（tumor mutational burden, TMB）存在明确关联。与TMB和PD-L1相比，在20种实体瘤中，帕博利珠单抗单药治疗后CFR与ORR的相关系数更高（斯皮尔曼相关系数r分别为0.69 vs 0.44和0.21）。在真实世界队列中，与低CFR患者相比，免疫组化检测显示高CFR的患者从免疫治疗中获益显著（风险比（hazard ratio, HR）为0.37；95%置信区间（95% confidence interval, 95%CI）为0.19~0.75；p<0.001）。
研究结论：CFR是一种全新且简便的参数，可用于识别无法从免疫治疗中获益的患者，未来仍需开展相关研究验证这一发现。