PURPOSE The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear. EXPERIMENTAL DESIGN We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing. RESULTS The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months. CONCLUSIONS EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.

中文翻译：

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EGFR-TKI治疗对EGFR突变阳性非小细胞肺癌的肿瘤免疫微环境的影响。

目的EGFR酪氨酸激酶抑制剂（TKI）对非小细胞肺癌（NSCLC）中肿瘤免疫微环境（TME）的影响尚不清楚。实验设计我们回顾性鉴定了138名EGFR突变型NSCLC患者，这些患者在EGFR-TKI治疗期间进展后接受了活检。通过IHC测定基线和进展后肿瘤细胞中PD-L1和CD73的表达以及肿瘤浸润淋巴细胞（TIL）的密度。通过下一代测序确定肿瘤突变负担（TMB）。结果PD-L1表达水平≥50％（高）的患者比例从EGFR-TKI前的14％增加到术后28％（P = 0.0010）。EGFR-TKI治疗后CD8 +和FOXP3 + TIL密度显着降低，而PD-L1表达水平高的肿瘤中CD8 + TIL密度得以维持。EGFR-TKI治疗后肿瘤细胞中CD73的表达高于PD-L1高表达患者。EGFR-TKI治疗后，TMB往往比以前高（3.3→4.1突变/ Mbp，P = 0.0508）。EGFR-TKI后高表达患者的PD-L1表达水平低的患者，其后用PD-1抗体进行后续治疗的中位无进展生存期更长（7.1 vs. 1.7个月，P = 0.0033），其中两个五名在EGFR-TKI治疗后PD-L1表达水平由低变高的患者实现了PFS> 6个月。结论EGFR-TKI治疗与EGFR突变的NSCLC的TME改变有关，这种改变可能为优化随后的PD-1抑制剂治疗提供线索。