Division of Medical Oncology for Melanoma & Sarcoma, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy.
Clin Cancer Res. 2021 Aug 1;27(15):4311-4324. doi: 10.1158/1078-0432.CCR-21-0136. Epub 2021 May 20.
We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC.
We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti-PD-1/anti-PD-L1 drugs.
As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell-excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti-PD-1/PD-L1 drugs.
We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.
我们之前证明性别会影响免疫检查点抑制剂的反应。在本文中，我们研究了非小细胞肺癌（NSCLC）患者的抗癌免疫反应和免疫逃逸的性别差异的分子机制。
我们分析了（i）来自七个不同数据集的 2575 例早期 NSCLC 的转录组数据；（ii）TRACERx 肺研究中 327 个分子水平广泛表征的肿瘤样本；（iii）分别接受抗 PD-1/抗 PD-L1 药物治疗的 329 例和 391 例晚期 NSCLC 患者的两个独立队列。
与男性相比，女性的肿瘤微环境（TME）中富含多种先天和适应性免疫细胞类型，包括特定的 T 细胞亚群。男性和女性的 NSCLC 利用了不同的免疫逃逸机制。女性的 TME 表现为 T 细胞功能障碍状态明显更严重，抑制性免疫检查点分子表达更高，以及包括癌症相关成纤维细胞、髓系来源抑制细胞和调节性 T 细胞在内的免疫抑制细胞丰度更高。相比之下，男性的 TME 明显富含 T 细胞排斥表型。我们报告了支持男性肿瘤中免疫系统新抗原呈递受损的数据，这是解释所观察到的发现的分子机制。最后，与我们的结果一致，我们显示了 TMB 与接受抗 PD-1/PD-L1 药物治疗的晚期 NSCLC 患者结局之间存在显著的性别差异。
我们证明了抗癌免疫反应和免疫逃逸机制存在有意义的性别差异，这可能被利用来提高女性和男性的免疫治疗效果。
