肿瘤微环境免疫功能与肺癌免疫治疗反应性关系及对预后的影响-东南大学学报医学版

肿瘤微环境免疫功能与肺癌免疫治疗反应性关系及对预后的影响

单位：安康市人民医院呼吸内科, 陕西安康 725000

关键词：肺癌程序性死亡蛋白1/程序性死亡蛋白配体1抑制剂治疗反应性肿瘤微环境免疫功能

分类号：R734;R392.1

出版年·卷·期（页码）：2026·45·第二期（246-255）

摘要：

目的:探讨肺癌抗程序性死亡蛋白1(PD-1)/程序性死亡蛋白配体1(PD-L1)不同治疗反应性患者治疗前肿瘤微环境宿主免疫功能差异性及对预后的影响。方法:选取本院2021年3月至2022年9月152例采用PD-1/PD-L1抑制剂治疗的肺癌患者,根据治疗反应性不同分为缓解组、稳定组、进展组,比较3组基线资料和治疗前肿瘤微环境宿主免疫功能,采用Logistic回归分析抗PD-1/PD-L1治疗反应性的影响因素,并绘制预测抗PD-1/PD-L1治疗反应性的列线图,采用Cox回归分析治疗前不同肿瘤微环境宿主免疫功能对生存预后的影响,应用K-M曲线分析治疗前不同肿瘤微环境宿主免疫功能患者的生存率。结果:缓解组PD-L1⁺CD8 肿瘤浸润淋巴细胞(TILs)高表达患者占比和CD56⁺自然杀伤(NK)细胞阳性患者占比高于稳定组、进展组,且稳定组高于进展组(P＜0.05);缓解组边缘型CD68⁺肿瘤相关巨噬细胞(TAMs)、中心型CD68⁺TAMs、边缘型CD163⁺TAMs、中心型CD163⁺TAMs高表达患者占比低于稳定组、进展组,且稳定组低于进展组(P＜0.05);多因素Logistic回归分析显示,将抗表皮生长因子受体(EGFR)药物进行校正后,PD-L1⁺CD8 TILs、CD56⁺NK细胞仍是治疗反应性的独立相关保护因素,边缘型CD68⁺TAMs、中心型CD68⁺TAMs、边缘型CD163⁺TAMs、中心型CD163⁺TAMs仍是治疗反应性的独立相关危险因素(P＜0.05);绘制列线图显示,基于PD-L1⁺CD8 TILs、CD56⁺NK细胞、边缘型CD68⁺TAMs、中心型CD68⁺TAMs、边缘型CD163⁺TAMs、中心型CD163⁺TAMs的列线图预测抗PD-1/PD-L1治疗反应性的C-index为0.954,对列线图预测效能进行验证显示,列线图对抗PD-1/PD-L1治疗反应性具有较高的预测价值(AUC=0.954,95%CI 0.919~0.989),且列线图预测结果与理想曲线相贴合,表明预测结果与临床实际之间差异无统计学意义,在较宽的阈值概率范围内,采用列线图预测抗PD-1/PD-L1治疗反应性具有临床净获益;Cox回归分析显示, PD-L1⁺CD8 TILs、CD56⁺NK细胞、边缘型CD68⁺TAMs、边缘型CD163⁺TAMs是生存预后的相关影响因素(P＜0.05);K-M分析显示,PD-L1⁺CD8 TILs高表达患者生存率低于低表达患者(P＜0.05),CD56⁺NK细胞阳性患者生存率高于阴性患者(P＜0.05),边缘型CD68⁺TAMs高表达患者生存率低于低表达患者(P＜0.05),边缘型CD163⁺TAMs高表达患者生存率低于低表达患者(P＜0.05)。结论:高浸润的PD-L1⁺CD8 TILs、CD56⁺NK细胞和低浸润的CD68⁺TAMs、CD163⁺TAMs与较佳的肺癌抗PD-1/PD-L1治疗应答有关,基于以上免疫功能指标构建的列线图在早期预测治疗反应性和生存预后方面具有潜在的价值。

Objective: To investigate the difference and significance of host immune function in tumor microenvironment before treatment in patients with different therapeutic response of anti-programmed death protein 1(PD-1)/programmed death protein ligand 1(PD-L1) in lung cancer. Methods: A total of 152 patients with lung cancer treated with PD-1/PD-L1 inhibitors from March 2021 to September 2022 were divided into a remission group, a stable group and a progressive group according to therapeutic response. The baseline data of the three groups and the host immune function of tumor microenvironment before treatment were compared. Logistic regression was used to analyze the influencing factors of anti-PD-1/PD-L1 therapeutic response, and a nomogram was drawn to predict the response to anti-PD-1/PD-L1 treatment. Cox regression analysis was used to analyze the effect of host immune function in different tumor microenvironment before treatment on survival and prognosis. K-M curve was used to analyze the survival rate of patients with different host immune functions in tumor microenvironment before treatment. Results: The proportion of patients with high expression of PD-L1⁺CD8 tumor infiltrating lymphocytes(TILs) and CD56⁺natural killer(NK) cells in the remission group was higher than that in the stable group and the progressive group, and the stable group was higher than the progressive group(P＜0.05); the proportion of patients with high expression of marginal CD68⁺tumor-associated macrophages(TAMs), central CD68⁺TAMs, marginal CD163⁺TAMs, central CD163⁺TAMs in the remission group was lower than that in the stable group and the progress group, and the stable group was lower than the progress group(P＜0.05).Multivariate Logistic regression analysis showed that PD-L1⁺CD8 TILs and CD56⁺NK cells were still independent related protective factors for therapeutic response after correction of anti-epidermal growth factor receptor(EGFR) drugs, while marginal CD68⁺TAMs, central CD68⁺TAMs, marginal CD163⁺TAMs and central CD163⁺TAMs were still independent related risk factors for therapeutic response(P＜0.05). The nomogram was drawn,it indicated that the C-index of the nomogram based on PD-L1⁺CD8 TILs, CD56⁺ NK cells, marginal CD68⁺TAMs, central CD68⁺TAMs, marginal CD163⁺TAMs, and central CD163⁺TAMs for predicting anti-PD-1/PD-L1 treatment response was 0.954. Validation of the nomogram's predictive performance showed that the nomogram had high predictive value for anti-PD-1/PD-L1 treatment response(AUC=0.954, 95%CI 0.919-0.989). Furthermore, the nomogram's predictive results were consistent with the ideal curve, indicating no statistically significant difference between the predicted results and clinical reality. Additionally, within a wide range of threshold probabilities, using the nomogram to predict anti-PD-1/PD-L1 treatment response provided clinical net benefit. Cox regression analysis showed that PD-L1⁺CD8 TILs, CD56⁺NK cells, marginal CD68⁺TAMs and marginal CD163⁺TAMs were related factors affecting survival and prognosis(P＜0.05). K-M analysis showed that the survival rate of patients with high expression of PD-L1⁺CD8 TILs was lower than that of patients with low expression(P＜0.05). The survival rate of CD56⁺NK cells positive patients was higher than that of negative patients(P＜0.05). The survival rate of patients with high marginal CD68⁺TAMs expression was lower than that of patients with low expression(P＜0.05). The survival rate of patients with high marginal CD163⁺TAMs expression was lower than that of patients with low expression(P＜0.05). Conclusion: Highly infiltrative PD-L1⁺CD8 TILs, CD56⁺NK cells, and lowly infiltrative CD68⁺TAMs, CD163⁺TAMs are associated with better response to anti-PD-1/PD-L1 therapy in lung cancer. The nomogram constructed based on these immune function indicators has potential value in early prediction of treatment responsiveness and survival prognosis.

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