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). 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. 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. 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.

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单细胞和批量测序揭示的性别差异及其对食管癌免疫治疗疗效的影响

关于性别是否影响免疫抑制性肿瘤微环境和免疫治疗一直存在争论。在这里，我们探讨了性别二态性的潜在分子基础及其对食管癌（EC）免疫治疗疗效的影响。来自 3 期试验的 2360 名 EC 患者被汇集起来，通过计算风险比 (HR) 及其 95% 置信区间 (CI) 来比较总体生存率。整合 1425 个样本的基因组数据来描述基因组景观和抗原特征。我们还根据 60 名患者 105,145 个免疫细胞的单细胞 RNA 测序和 T 细胞受体测序数据检查了性别差异。免疫治疗与男性的良好结局相关（HR，0.71；95% CI，0.65-0.79；P < 0.001），但与女性无关（HR，0.98；95% CI，0.78-1.23；P = 0.84）（Pinteraction = 0.02）。男性和女性之间 8 个基因突变、12 个单碱基替换特征和 131 个反应组途径的频率存在显着差异。此外，女性中富含 HLA-II 抗原的六种亚型。因此，我们构建并验证了与性别相关的特征，以更好地预测免疫治疗的结果。耗尽的 CD8+ T 细胞在男性中高度浸润，而幼稚 CD8+ T 细胞在女性中更为常见。对多种恶性肿瘤的进一步检查表明，对免疫治疗有反应的患者体内耗尽的 CD8+ T 细胞增多。我们的研究描绘了 EC 中巨大的基因组和细胞性别差异。此外，男性（而不是女性）从免疫治疗中获得了显着的益处。这些结果对治疗决策和开发个性化护理的免疫疗法具有影响。近年来，免疫治疗逐渐取代传统化疗成为食管癌的标准治疗方法。众所周知，男性和女性的免疫反应存在显着差异。然而，关于性别是否会影响免疫疗法的治疗结果一直存在争论。在本研究中，我们系统地描述了食管癌的基因组和细胞景观，并揭示了男性和女性患者之间的显着差异。此外，通过对 2000 多名食道癌患者的研究，我们发现只有男性才能从免疫疗法中受益。在女性中，免疫疗法未能表现出优于化疗的效果。这些结果对治疗决策和开发用于个性化护理的下一代免疫疗法具有影响。