Azienda Ospedale Università di Padova.
Veneto Institute of Oncology (IOV-IRCCS).
Int J Surg. 2023 Mar 1;109(3):323-332. doi: 10.1097/JS9.0000000000000214.
Studies evaluating sex differences in colorectal cancer (CRC) tumor microenvironment are limited, and no previous study has focused on rectal cancer patients' constitutive immune surveillance mechanisms. The authors aimed to assess gender-related differences in the immune microenvironment of rectal cancer patients.
A systematic review and meta-analysis were conducted up to 31 May 2021, including studies focusing on gender-related differences in the CRC tumor microenvironment. Data on the mutational profile of rectal cancer were extracted from the Cancer Genome Atlas (TCGA). A subanalysis of the two IMMUNOREACT trials (NCT04915326 and NCT04917263) was performed, aiming to detect gender-related differences in the immune microenvironment of the healthy mucosa in patients with early (IMMUNOREACT 1 cohort) and locally advanced rectal cancer following neoadjuvant therapy (IMMUNOREACT 2 cohort). In the retrospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 442 patients (177 female and 265 male), while in the retrospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), we enrolled 264 patients (80 female and 184 male). In the prospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 72 patients (26 female and 46 male), while in the prospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), the authors enrolled 105 patients (42 female and 63 male).
Seven studies reported PD-L1 expression in the CRC microenvironment, but no significant difference could be identified between the sexes. In the TGCA series, mutations of SYNE1 and RYR2 were significantly more frequent in male patients with rectal cancer. In the IMMUNOREACT 1 cohort, male patients had a higher expression of epithelial cells expressing HLA class I, while female patients had a higher number of activated CD4+Th1 cells. Female patients in the IMMUNOREACT 2 cohort showed a higher infiltration of epithelial cells expressing CD86 and activated cytotoxic T cells (P=0.01).
Male patients have more frequent oncogene mutations associated with a lower expression of T-cell activation genes. In the healthy mucosa of female patients, more Th1 cells and cytotoxic T cells suggest a potentially better immune response to the tumor. Sex should be considered when defining the treatment strategy for rectal cancer patients or designing prognostic scores.
评估结直肠癌（CRC）肿瘤微环境中性别差异的研究有限，以前没有研究关注直肠癌患者的固有免疫监视机制。作者旨在评估直肠癌患者免疫微环境中的性别相关差异。
系统评价和荟萃分析截至 2021 年 5 月 31 日，包括关注 CRC 肿瘤微环境中性别相关差异的研究。从癌症基因组图谱（TCGA）中提取直肠癌突变特征数据。对两项 IMMUNOREACT 试验（NCT04915326 和 NCT04917263）进行了亚分析，旨在检测接受新辅助治疗后早期（IMMUNOREACT 1 队列）和局部晚期直肠癌患者健康黏膜中免疫微环境的性别相关差异（IMMUNOREACT 2 队列）。在回顾性 IMMUNOREACT 1 队列（未接受治疗）中，作者纳入了 442 名患者（177 名女性和 265 名男性），而在回顾性 IMMUNOREACT 2 队列（接受新辅助治疗的患者）中，作者纳入了 264 名患者（80 名女性和 184 名男性）。在前瞻性 IMMUNOREACT 1 队列（未接受治疗）中，作者纳入了 72 名患者（26 名女性和 46 名男性），而在前瞻性 IMMUNOREACT 2 队列（接受新辅助治疗的患者）中，作者纳入了 105 名患者（42 名女性和 63 名男性）。
有 7 项研究报告了 CRC 微环境中的 PD-L1 表达，但男女之间没有显著差异。在 TCGA 系列中，SYNE1 和 RYR2 的突变在男性直肠癌患者中更为频繁。在 IMMUNOREACT 1 队列中，男性患者表达 HLA Ⅰ类的上皮细胞表达水平较高，而女性患者表达的激活 CD4+Th1 细胞较多。在 IMMUNOREACT 2 队列中，女性患者表达 CD86 和激活的细胞毒性 T 细胞的上皮细胞浸润程度更高（P=0.01）。
男性患者有更多与 T 细胞激活基因表达降低相关的致癌基因突变。在女性患者的健康黏膜中，更多的 Th1 细胞和细胞毒性 T 细胞提示对肿瘤的潜在更好的免疫反应。在为直肠癌患者制定治疗策略或设计预后评分时，应考虑性别因素。
