Spatial Tumor Immune Microenvironment as a Prognostic and Predictive Biomarker in Anti-EGFR-Based Maintenance for RAS wt Metastatic CRC-The PanaMa (AIO KRK0212) Trial.

This study analyzed the spatially resolved tumor immune microenvironment for prognostic and predictive impact in patients with RAS wild-type metastatic colorectal cancer receiving 5-fluoruracil/folinic acid ± panitumumab (Pmab) maintenance after Pmab + fluorouracil, folinic acid, and oxaliplatin induction (PanaMa AIO KRK0212; NCT01991873).

本研究分析了接受5-氟尿嘧啶/叶酸±帕尼单抗(Pmab)维持治疗的RAS野生型转移性结直肠癌患者的肿瘤免疫微环境的空间解析，以评估其预后和预测影响，这些患者在Pmab+氟尿嘧啶、叶酸和奥沙利铂诱导治疗后接受治疗（PanaMa AIO KRK0212; NCT01991873）。

patients_and_methods

Twelve immune parameters (lymphocyte markers: CD3, CD8, CD45RO, FOXP3, CD20, granzyme B, and perforin; immune checkpoints: PD-1, PD-L1, IDO1, and LAG3; and monocyte marker CD163) were quantified in spatially resolved tumor and stroma regions [invasive-margin (Inv) and center (Cen)] on tissue microarrays from available surgical resections using digital pathology.

在组织微阵列中，使用数字病理学对可获得的手术切除标本的空间解析肿瘤和基质区域（侵袭边缘（Inv）和中心（Cen））中的12个免疫参数（淋巴细胞标记物：CD3、CD8、CD45RO、FOXP3、CD20、颗粒酶B和穿孔素；免疫检查点：PD-1、PD-L1、IDO1和LAG3；以及单核细胞标记物CD163）进行了定量。

Prognostic and predictive associations were assessed using percentile cutoffs, immunoscore (IS), PD-L1 combined positive score, and an immunoactivation score (IAS).

使用百分位数截断值、免疫评分（IS）、PD-L1联合阳性评分和免疫激活评分（IAS）评估了预后和预测性关联。

The median progression-free (PFS) and overall survival(OS) were estimated by the Kaplan-Meier method, log rank test, and Cox regression.

通过Kaplan-Meier方法、log rank检验和Cox回归估计了中位无进展生存期（PFS）和总生存期（OS）。

Results

In 194 patients, low CD163 and high PD-1 in the tumor center were independent prognostic factors for prolonged PFS, whereas high central LAG3 was associated with improved OS.

在194名患者中，肿瘤中心CD163低表达和PD-1高表达是延长无进展生存期（PFS）的独立预后因素，而中央LAG3高表达与总生存期（OS）改善相关。

Pmab maintenance conferred PFS benefit in patients with low CD3InvStr, CD8Inv, LAG3CenTum, CD163CenTum, and IS and high CD45ROCen.

Pmab维持治疗在CD3浸润低、CD8浸润低、LAG3中心肿瘤低、CD163中心肿瘤低和IS低的患者中带来了无进展生存（PFS）的益处，以及CD45RO中心高表达的患者。

CD45ROCen high and LAG3Cen low also predicted OS benefit.

CD45RO中心高表达和LAG3中心低表达也预测了总生存（OS）的益处。

A positive IAS (≥2 predictive markers) identified patients deriving significant PFS (HR = 0.50; 95% confidence interval, 0.32-0.76; P < 0.001) and OS (HR = 0.54; 95% confidence interval, 0.33-0.86; P = 0.009) benefit from Pmab.

IAS阳性（≥2个预测标志物）识别出从Pmab治疗中显著获益的患者，其无进展生存期（PFS）（风险比HR = 0.50；95%置信区间，0.32-0.76；P < 0.001）和总生存期（OS）（HR = 0.54；95%置信区间，0.33-0.86；P = 0.009）都有显著改善。

Conclusions

Immune microenvironment factors, including CD3, CD8, CD163, LAG3, CD45RO, IS, and IAS, predict benefit from Pmab maintenance, suggesting immune activation as a key component of anti-EGFR efficacy.

包括CD3、CD8、CD163、LAG3、CD45RO、IS和IAS在内的免疫微环境因素预测了从Pmab维持治疗中获益的情况，这表明免疫激活是抗EGFR疗效的关键组成部分。