Despite a characteristic indolent course, a substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. Cells in the microenvironment may be a key contributor to treatment failure. We used a discovery and validation study design to identify microenvironmental determinants of early failure and then integrated these results into the FLIPI. In total, 496 newly diagnosed FL grade 1–3 A patients who were prospectively enrolled into the MER cohort from 2002 to 2012 were evaluated. Tissue microarrays were stained for CD4, CD8, FOXP3, CD32b, CD14, CD68, CD70, SIRP-α, TIM3, PD-1, and PD-L1. Early failure was defined as failing to achieve event-free survival at 24 months (EFS24) in immunochemotherapy-treated patients and EFS12 in all others. CyTOF and CODEX analysis were performed to characterize intratumoral immunophenotypes. Lack of intrafollicular CD4 expression was the only predictor of early failure that replicated with a pooled OR 2.37 (95%CI 1.48–3.79). We next developed a bio-clinical risk model (BioFLIPI), where lack of CD4 intrafollicular expression moved patients up one FLIPI risk group, adding a new fourth high-risk group. Compared with BioFLIPI score of 1, patients with a score of 2 (OR 2.17; 95% CI 1.08–4.69), 3 (OR 3.53; 95% CI 1.78–7.54), and 4 (OR 8.92; 95% CI 4.00–21.1) had increasing risk of early failure. The favorable intrafollicular CD4 T cells were identified as activated central memory T cells, whose prognostic value was independent from genetic features. In conclusion, lack of intrafollicular CD4 expression predicts early failure in FL and combined with FLIPI improves identification of high-risk patients; however, independent validation is warranted.

尽管具有特征性的惰性病程，但大部分滤泡性淋巴瘤（FL）患者早期复发且预后不佳。微环境中的细胞可能是治疗失败的关键因素。我们使用发现和验证研究设计来识别早期故障的微环境决定因素，然后将这些结果整合到 FLIPI 中。总共对 2002 年至 2012 年前瞻性纳入 MER 队列的 496 名新诊断 FL 1-3 A 级患者进行了评估。对组织微阵列进行 CD4、CD8、FOXP3、CD32b、CD14、CD68、CD70、SIRP-α、TIM3、PD-1 和 PD-L1 染色。早期失败定义为接受免疫化疗治疗的患者未能达到 24 个月无事件生存期 (EFS24)，而所有其他患者未能达到 EFS12。进行 CyTOF 和 CODEX 分析来表征瘤内免疫表型。滤泡内 CD4 表达缺乏是早期失败的唯一预测因素，合并 OR 为 2.37 (95% CI 1.48–3.79)。接下来，我们开发了一种生物临床风险模型 (BioFLIPI)，其中滤泡内 CD4 表达的缺乏使患者上升到一个 FLIPI 风险组，从而增加了一个新的第四个高风险组。与 BioFLIPI 评分为 1 分相比，评分为 2 分（OR 2.17；95% CI 1.08–4.69）、3 分（OR 3.53；95% CI 1.78–7.54）和 4 分（OR 8.92；95% CI 4.00–21.1）的患者）早期失败的风险不断增加。有利的滤泡内 CD4 T 细胞被鉴定为激活的中央记忆 T 细胞，其预后价值独立于遗传特征。总之，滤泡内 CD4 表达缺乏可预测 FL 早期失败，与 FLIPI 结合可提高高危患者的识别；然而，独立验证是有必要的。