Sex disparities revealed by single-cell and bulk sequencing and their impacts on the efficacy of immunotherapy in esophageal cancer.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Huimeng Yan, Jinyuan Huang, Yingying Li, Bin Zhao
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引用次数: 0

Abstract

Background: There is an ongoing debate on whether sex affects immune-suppressive tumor microenvironment and immunotherapy. Here, we explored the underlying molecular bases for sex dimorphisms and their impact on the efficacy of immunotherapy in esophageal cancer (EC).

Methods: 2360 EC patients from phase 3 trials were pooled to compare overall survivals by calculating hazard ratios (HRs) and their 95% confidence intervals (CIs). Genomic data of 1425 samples were integrated to depict the genomic landscapes and antigenic features. We also examined the sex disparities based on single-cell RNA sequencing and T cell receptor-sequencing data from 105,145 immune cells in 60 patients.

Results: Immunotherapy was associated with favorable outcomes in men (HR, 0.71; 95% CI, 0.65-0.79; P < 0.001), but not in women (HR, 0.98; 95% CI, 0.78-1.23; P = 0.84) (Pinteraction =0.02). The frequencies of 8 gene mutations, 12 single base substitutions signatures, and 131 reactome pathways were significantly different between male and female. Additionally, six subtypes of HLA-II antigens were enriched in women. Hence, we constructed and then validated a sex-related signature to better predict the outcomes of immunotherapy. Exhausted CD8+ T cells were highly infiltrated in men, while naïve CD8+ T cells were more common in women. Further examinations on multiple malignancies suggested exhausted CD8+ T cells were enriched in patients who responded to immunotherapy.

Conclusions: Our study delineated the robust genomic and cellular sex disparities in EC. Furthermore, male, rather than female, derived significantly benefits from immunotherapy. These results have implications for treatment decision-making and developing immunotherapy for personalized care. In the past several years, immunotherapy has gradually replaced the traditional chemotherapy as the standard treatment in esophageal cancer. It is well-established that immunological responses in male and female differ significantly. However, there is an ongoing debate on whether sex can impact the treatment outcomes in immunotherapy. In the present study, we systematically characterized the genomic and cellular landscapes of esophageal cancer, and revealed the significant differences between male and female patients. Furthermore, with over 2000 patients with esophageal cancer, we showed that only men can benefit from immunotherapy. In women, immunotherapy failed to show superior over chemotherapy. These results have implications for treatment decision-making and developing next-generation immunotherapy for personalized care.

单细胞和大量测序揭示的性别差异及其对食管癌免疫疗法疗效的影响。
背景:关于性别是否会影响免疫抑制性肿瘤微环境和免疫疗法的争论一直存在。在此,我们探讨了性别二态性的分子基础及其对食管癌(EC)免疫疗法疗效的影响。方法:我们汇总了来自3期试验的2360例食管癌患者,通过计算危险比(HRs)及其95%置信区间(CIs)来比较总生存率。我们整合了1425个样本的基因组数据,以描绘基因组图谱和抗原特征。我们还根据单细胞RNA测序和60例患者105,145个免疫细胞的T细胞受体测序数据研究了性别差异:结果:免疫治疗与男性患者的良好预后相关(HR,0.71;95% CI,0.65-0.79;P交互作用=0.02)。男性和女性在8种基因突变、12种单碱基置换特征和131种反应组通路的频率上存在显著差异。此外,女性富集了六种 HLA-II 抗原亚型。因此,我们构建并验证了与性别相关的特征,以更好地预测免疫疗法的结果。衰竭的 CD8+ T 细胞在男性中高度浸润,而幼稚的 CD8+ T 细胞在女性中更为常见。对多种恶性肿瘤的进一步研究表明,对免疫疗法有反应的患者体内富集了衰竭的CD8+ T细胞:我们的研究揭示了EC在基因组和细胞方面的显著性别差异。此外,男性比女性更容易从免疫疗法中获益。这些结果对治疗决策和开发个性化治疗的免疫疗法具有重要意义。在过去几年中,免疫疗法已逐渐取代传统化疗,成为食管癌的标准治疗方法。男性和女性的免疫反应明显不同,这一点已得到公认。然而,关于性别是否会影响免疫疗法的治疗效果,一直存在争议。在本研究中,我们系统地描述了食管癌的基因组和细胞图谱,并揭示了男性和女性患者之间的显著差异。此外,通过对 2000 多名食管癌患者的研究,我们发现只有男性才能从免疫疗法中获益。在女性患者中,免疫疗法未能显示出优于化疗的效果。这些结果对治疗决策和开发用于个性化治疗的下一代免疫疗法具有重要意义。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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