Distinct regulation mechanism of immune-related genes in left-sided and right-sided colon cancer

Colon cancer is one of the most common cancers in worldwide. Emerging evidence has demonstrated distinct patterns of immune infiltration between left colon cancer (LCC) and right colon cancer (RCC), classified according to primary tumor location. However, the underlying mechanism was still unknown. Here, we identified 111 more up-regulated genes (MURGs) including PD1 (PDCD1) and CTLA4 in RCC and 166 more down-regulated genes (MDRGs) in LCC, all participating in immune-related biological processes. Notably, CD83, CXCR4 and ISL1 emerged as reversely regulated immune-related genes (IRGs) showing opposite regulation patterns between the two cancer types. Through regulatory network analysis, we found that genetic mutations predominantly drive enhanced immune infiltration in RCC through IRG up-regulation, whereas DNA methylation-mediated IRG suppression accounts for diminished immune responses in LCC. Furthermore, prognostic models based on these IRGs with high-quality were constructed in LCC and RCC respectively. In conclusion, our results provide crucial insights into the divergent immunoregulatory mechanisms governing LCC and RCC, potentially facilitating the discovery of novel biomarkers for prognosis prediction and targeted therapy.

结肠癌是全球范围内最常见的恶性肿瘤之一。越来越多的研究证据表明，依据原发肿瘤部位分型的左半结肠癌（left colon cancer, LCC）与右半结肠癌（right colon cancer, RCC），二者免疫浸润模式存在显著差异。然而，二者免疫浸润差异的潜在调控机制仍未明确。本研究在右半结肠癌中筛选得到111个相较于左半结肠癌的上调差异基因（more up-regulated genes, MURGs），其中包含PD1（PDCD1）与CTLA4；同时在左半结肠癌中筛选得到166个相较于右半结肠癌的下调差异基因（more down-regulated genes, MDRGs），上述基因均参与免疫相关生物学过程。值得注意的是，CD83、CXCR4与ISL1作为反向调控免疫相关基因（immune-related genes, IRGs），在两种结肠癌中呈现完全相反的表达调控模式。通过调控网络分析，本研究发现：遗传突变主要通过上调免疫相关基因，增强右半结肠癌的免疫浸润水平；而DNA甲基化介导的免疫相关基因抑制，则是左半结肠癌免疫应答减弱的核心原因。此外，本研究分别基于上述高质量免疫相关基因，构建了针对左半结肠癌与右半结肠癌的预后预测模型。综上，本研究结果为解析左半结肠癌与右半结肠癌的差异化免疫调控机制提供了重要理论依据，有望为预后预测与靶向治疗的新型生物标志物开发提供新的思路。