Department of Translational Molecular Pathology, Unit 951, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Blvd, Houston, TX, 77030, USA.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Immunother Cancer. 2018 Jun 6;6(1):48. doi: 10.1186/s40425-018-0368-0.
The clinical efficacy observed with inhibitors of programed cell death 1/programed cell death ligand 1 (PD-L1/PD-1) in cancer therapy has prompted studies to characterize the immune response in several tumor types, including lung cancer. However, the immunological profile of non-small cell lung carcinoma (NSCLC) treated with neoadjuvant chemotherapy (NCT) is not yet fully characterized, and it may be therapeutically important. The aim of this retrospective study was to characterize and quantify PD-L1/PD-1 expression and tumor-associated immune cells (TAICs) in surgically resected NSCLCs from patients who received NCT or did not receive NCT (non-NCT).
We analyzed immune markers in formalin-fixed, paraffin-embedded tumor tissues resected from 112 patients with stage II/III NSCLC, including 61 non-NCT (adenocarcinoma [ADC] = 33; squamous cell carcinoma [SCC] = 28) and 51 NCT (ADC = 31; SCC = 20). We used multiplex immunofluorescence to identify and quantify immune markers grouped into two 6-antibody panels: panel 1 included AE1/AE3, PD-L1, CD3, CD4, CD8, and CD68; panel 2 included AE1/AE3, PD1, granzyme B, FOXP3, CD45RO, and CD57.
PD-L1 expression was higher (> overall median) in NCT cases (median, 19.53%) than in non-NCT cases (median, 1.55%; P = 0.022). Overall, density of TAICs was higher in NCT-NSCLCs than in non-NCT-NSCLCs. Densities of CD3+ cells in the tumor epithelial compartment were higher in NCT-ADCs and NCT-SCCs than in non-NCT-ADCs and non-NCT-SCCs (P = 0.043). Compared with non-NCT-SCCs, NCT-SCCs showed significantly higher densities of CD3 + CD4+ (P = 0.019) and PD-1+ (P < 0.001) cells in the tumor epithelial compartment. Density of CD68+ tumor-associated macrophages (TAMs) was higher in NCT-NSCLCs than in non-NCT-NSCLCs and was significantly higher in NCT-SCCs than in non-NCT-SCCs. In NCT-NSCLCs, higher levels of epithelial T lymphocytes (CD3 + CD4+) and epithelial and stromal TAMs (CD68+) were associated with better outcome in univariate and multivariate analyses.
NCT-NSCLCs exhibited higher levels of PD-L1 expression and T-cell subset regulation than non-NCT-NSCLCs, suggesting that NCT activates specific immune response mechanisms in lung cancer. These results suggest the need for clinical trials and translational studies of combined chemotherapy and immunotherapy prior to surgical resection of locally advanced NSCLC.
程序性细胞死亡 1/程序性细胞死亡配体 1（PD-L1/PD-1）抑制剂在癌症治疗中的临床疗效促使人们对包括肺癌在内的多种肿瘤类型的免疫反应进行了特征描述。然而，接受新辅助化疗（NCT）的非小细胞肺癌（NSCLC）的免疫特征尚未完全描述，这可能具有治疗意义。本回顾性研究的目的是对接受 NCT 或未接受 NCT（非-NCT）治疗的 NSCLC 患者手术切除的肿瘤组织中 PD-L1/PD-1 表达和肿瘤相关免疫细胞（TAIC）进行特征描述和定量分析。
我们分析了 112 例 II/III 期 NSCLC 患者的福尔马林固定、石蜡包埋肿瘤组织中的免疫标志物，包括 61 例非-NCT（腺癌 [ADC] = 33；鳞状细胞癌 [SCC] = 28）和 51 例 NCT（ADC = 31；SCC = 20）。我们使用多重免疫荧光法来鉴定和定量分为两个 6 抗体组的免疫标志物：第 1 组包括 AE1/AE3、PD-L1、CD3、CD4、CD8 和 CD68；第 2 组包括 AE1/AE3、PD1、颗粒酶 B、FOXP3、CD45RO 和 CD57。
NCT 病例的 PD-L1 表达（中位数，19.53%）高于非-NCT 病例（中位数，1.55%；P=0.022）。总体而言，NCT-NSCLC 中的 TAIC 密度高于非-NCT-NSCLC。NCT-ADC 和 NCT-SCC 肿瘤上皮区的 CD3+细胞密度高于非-NCT-ADC 和非-NCT-SCC（P=0.043）。与非-NCT-SCC 相比，NCT-SCC 肿瘤上皮区的 CD3+CD4+（P=0.019）和 PD-1+（P<0.001）细胞密度明显更高。NCT-NSCLC 中的 CD68+肿瘤相关巨噬细胞（TAM）密度高于非-NCT-NSCLC，NCT-SCC 中的 TAM 密度明显高于非-NCT-SCC。在 NCT-NSCLC 中，上皮 T 淋巴细胞（CD3+CD4+）和上皮及基质 TAM（CD68+）水平较高与单因素和多因素分析中的生存获益相关。
NCT-NSCLC 比非-NCT-NSCLC 表达更高水平的 PD-L1 和 T 细胞亚群调节，提示 NCT 在肺癌中激活了特定的免疫反应机制。这些结果表明，在局部晚期 NSCLC 手术切除前，需要进行化疗和免疫联合治疗的临床试验和转化研究。
