Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Universidad de Barcelona, Barcelona, Spain.
Clin Cancer Res. 2022 Jun 1;28(11):2461-2473. doi: 10.1158/1078-0432.CCR-21-3207.
Our understanding of the immunopathology of resectable non-small cell lung cancer (NSCLC) is still limited. Here, we explore immune programs that inform of tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in localized NSCLC.
Targeted immune gene sequencing using the HTG Precision Immuno-Oncology panel was performed in localized NSCLCs from three cohorts based on treatment: naïve (n = 190), neoadjuvant chemotherapy (n = 38), and neoadjuvant chemoimmunotherapy (n = 21). Tumor immune microenvironment (TIME) phenotypes were based on the location of CD8+ T cells (inflamed, cold, excluded), tumoral PD-L1 expression (<1% and ≥1%), and tumor-infiltrating lymphocytes (TIL). Immune programs and signatures were statistically analyzed on the basis of tumoral PD-L1 expression, immune phenotypes, and pathologic response and were cross-compared across the three cohorts.
PD-L1-positive tumors exhibited increased signature scores for various lymphoid and myeloid cell subsets (P < 0.05). TIME phenotypes exhibited disparate frequencies by stage, PD-L1 expression, and mutational burden. Inflamed and PD-L1+/TILs+ NSCLCs displayed overall significantly heightened levels of immune signatures, with the excluded group representing an intermediate state. A cytotoxic T-cell signature was associated with favorable survival in neoadjuvant chemotherapy-treated NSCLCs (P < 0.05). Pathologic response to chemoimmunotherapy was positively associated with higher expression of genes involved in immune activation, chemotaxis, as well as T and natural killer cells (P < 0.05 for all). Among the three cohorts, chemoimmunotherapy-treated NSCLCs exhibited the highest scores for various immune cell subsets including T effector and B cells (P < 0.05).
Our findings highlight immune gene programs that may underlie host tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC.
我们对可切除非小细胞肺癌（NSCLC）的免疫病理学的理解仍然有限。在这里，我们探讨了在局部 NSCLC 中与肿瘤免疫以及对新辅助化疗和化疗免疫治疗的反应相关的免疫程序。
对三个治疗组别的局部 NSCLC 进行了靶向免疫基因测序：未治疗组（n=190）、新辅助化疗组（n=38）和新辅助化疗免疫治疗组（n=21）。基于 CD8+T 细胞的位置（炎症、冷、排除）、肿瘤 PD-L1 表达（<1%和≥1%）和肿瘤浸润淋巴细胞（TIL）来确定肿瘤免疫微环境（TIME）表型。基于肿瘤 PD-L1 表达、免疫表型以及病理反应对免疫程序和特征进行了统计学分析，并在三组之间进行了交叉比较。
PD-L1 阳性肿瘤的各种淋巴和髓样细胞亚群的特征评分增加（P<0.05）。TIME 表型在不同的阶段、PD-L1 表达和突变负担方面存在不同的频率。炎症和 PD-L1+/TILs+NSCLC 表现出整体显著升高的免疫特征水平，而排除组则代表中间状态。细胞毒性 T 细胞特征与新辅助化疗治疗的 NSCLC 的良好生存相关（P<0.05）。对化疗免疫治疗的病理反应与参与免疫激活、趋化作用以及 T 细胞和自然杀伤细胞的基因表达较高呈正相关（所有 P<0.05）。在三组中，化疗免疫治疗的 NSCLC 具有最高的各种免疫细胞亚群得分，包括 T 效应细胞和 B 细胞（所有 P<0.05）。
我们的研究结果突出了可能是可切除 NSCLC 中宿主肿瘤免疫和对新辅助化疗及化疗免疫治疗反应的基础的免疫基因程序。
