OBJECTIVES The efficacy of immunotherapy in epidermal growth factor receptor (EGFR)-activating non-small cell lung cancer (NSCLC) is limited. However, a series of patients with uncommon EGFR alterations was reported to derive clinical benefit from PD-1 blockade. To characterize the tumor immune microenvironment, we retrospectively evaluated tumor PD-L1 expression and T cells infiltration among NSCLC patients with uncommon EGFR mutations. MATERIALS AND METHODS Immunohistochemistry was used to analyze the expression of PD-L1 and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs). Chi-square test and Cox proportional hazards regression were conducted to investigate the correlations between the immune microenvironment features and clinicopathological variables and survival, as well as to explore the potential of immunotherapy in this patient population. RESULTS Among 600 NSCLC patients with EGFR alterations, we identified 49 (8.2 %) bearing uncommon mutations, including G719X, L861Q, S768I, and Ex20 ins. In total, 49.0 % (24/49) of these patients showed positive PD-L1 expression in tumor cells, markedly higher than the proportion in patients with classic sensitive mutations (19del and L858R, 12.2 % [67/551], P < 0.05). Furthermore, PD-L1 expression was associated with relatively short overall survival (OS; 15.2 vs 29.3 months, P = 0.006) and was identified as an independent predictor of OS (hazard ratio=2.57, 95 % confidence interval: 1.03-7.12, P = 0.045). Additionally, PD-L1 positivity was predominantly observed among tumors with CD8+ TILs infiltration (P = 0.001). Uncommon EGFR-mutant tumors had a high frequency (36.7 %) of concurrent PD-L1 expression and abundant CD8 + TILs infiltration. Moreover, this dual-positive group exhibited the most unfavorable prognosis (P = 0.023). Notably, patients with PD-L1 and CD8 dual positivity showed a favorable response to PD-1 inhibitors. CONCLUSIONS High rates of concomitant PD-L1 expression and CD8 + TILs within the tumor microenvironment were observed in NSCLC patients with uncommon EGFR mutations. Further investigations are needed to confirm the therapeutic sensitivity to PD-1 blockade in this subgroup.

中文翻译：

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罕见的EGFR突变非小细胞肺癌患者的PD-L1表达和T细胞浸润以及对免疫治疗的反应。

目的免疫治疗表皮生长因子受体（EGFR）激活的非小细胞肺癌（NSCLC）的疗效有限。然而，据报道一系列具有罕见EGFR改变的患者可从PD-1阻滞中获得临床益处。为了表征肿瘤的免疫微环境，我们回顾性评估了EGFR突变少的NSCLC患者的肿瘤PD-L1表达和T细胞浸润。材料与方法采用免疫组织化学方法分析PD-L1的表达以及CD4 +和CD8 +肿瘤浸润淋巴细胞（TILs）的丰度。进行卡方检验和Cox比例风险回归分析，以研究免疫微环境特征与临床病理变量和生存率之间的相关性，以及探索该患者人群中免疫疗法的潜力。结果在600名EGFR改变的NSCLC患者中，我们鉴定出49个（8.2％）携带罕见突变，包括G719X，L861Q，S768I和Ex20 ins。这些患者中，共有49.0％（24/49）的患者在肿瘤细胞中显示PD-L1阳性表达，明显高于经典敏感突变患者的比例（19del和L858R，12.2％[67/551]，P <0.05 ）。此外，PD-L1表达与相对较短的总生存期有关（OS； 15.2 vs 29.3个月，P = 0.006），并被确定为OS的独立预测因子（危险比= 2.57，95％置信区间：1.03-7.12，P = 0.045）。此外，在CD8 + TILs浸润的肿瘤中主要观察到PD-L1阳性（P = 0.001）。罕见的EGFR突变肿瘤高频率（36.7％）的并发PD-L1表达和丰富的CD8 + TILs浸润。此外，该双重阳性组的预后最差（P = 0.023）。值得注意的是，PD-L1和CD8双重阳性的患者对PD-1抑制剂表现出良好的反应。结论在具有罕见EGFR突变的NSCLC患者中，在肿瘤微环境中观察到较高的伴随PD-L1表达和CD8 + TILs。需要进一步的研究来确认该亚组对PD-1阻滞剂的治疗敏感性。PD-L1和CD8双重阳性患者对PD-1抑制剂表现出良好的反应。结论在具有罕见EGFR突变的NSCLC患者中，在肿瘤微环境中观察到较高的伴随PD-L1表达和CD8 + TILs。需要进一步的研究来确认该亚组对PD-1阻滞剂的治疗敏感性。PD-L1和CD8双重阳性患者对PD-1抑制剂表现出良好的反应。结论在具有罕见EGFR突变的NSCLC患者中，在肿瘤微环境中观察到较高的伴随PD-L1表达和CD8 + TILs。需要进一步的研究以确认该亚组对PD-1阻滞剂的治疗敏感性。