Liu Dongfang, Li Chen, Deng Zenghua, Luo Nan, Li Wenxia, Hu Wenzhe, Li Xiang, Qiu Zichao, Chen Jianfei, Peng Jirun
Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Ninth School of Clinical Medicine, Peking University, Beijing, China.
Front Med (Lausanne). 2024 Aug 29;11:1403171. doi: 10.3389/fmed.2024.1403171. eCollection 2024.
Distinct clinical features and molecular characteristics of left-sided colon cancer (LCC) and right-sided colon cancer (RCC) suggest significant variations in their tumor microenvironments (TME). These differences can impact the efficacy of immunotherapy, making it essential to investigate and understand these disparities.
We conducted a multi-omics analysis, including bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing (WES), to investigate the constituents and characteristic differences of the tumor microenvironment (TME) in left-sided colon cancer (LCC) and right-sided colon cancer (RCC).
Deconvolution algorithms revealed significant differences in infiltrated immune cells between left-sided colon cancer (LCC) and right-sided colon cancer (RCC), including dendritic cells, neutrophils, natural killer (NK) cells, CD4 and CD8 T cells, and M1 macrophages (P < 0.05). Notably, whole-exome sequencing (WES) data analysis showed a significantly higher mutation frequency in RCC compared to LCC (82,187/162 versus 18,726/115, < 0.01). Single-cell analysis identified predominant tumor cell subclusters in RCC characterized by heightened proliferative potential and increased expression of major histocompatibility complex class I molecules. However, the main CD8 + T cell subpopulations in RCC exhibited a highly differentiated state, marked by T cell exhaustion and recent activation, defined as tumor-specific cytotoxic T lymphocytes (CTLs). Immunofluorescence and flow cytometry results confirmed this trend. Additionally, intercellular communication analysis demonstrated a greater quantity and intensity of interactions between tumor-specific CTLs and tumor cells in RCC.
RCC patients with an abundance of tumor-specific cytotoxic T lymphocytes (CTLs) and increased immunogenicity of tumor cells in the TME may be better candidates for immune checkpoint inhibitor therapy.
左半结肠癌（LCC）和右半结肠癌（RCC）不同的临床特征和分子特性表明它们的肿瘤微环境（TME）存在显著差异。这些差异会影响免疫治疗的疗效，因此有必要研究和了解这些差异。
我们进行了多组学分析，包括 bulk RNA 测序（bulk RNA-seq）、单细胞 RNA 测序（scRNA-seq）和全外显子测序（WES），以研究左半结肠癌（LCC）和右半结肠癌（RCC）肿瘤微环境（TME）的组成成分和特征差异。
反卷积算法显示，左半结肠癌（LCC）和右半结肠癌（RCC）之间浸润的免疫细胞存在显著差异，包括树突状细胞、中性粒细胞、自然杀伤（NK）细胞、CD4 和 CD8 T 细胞以及 M1 巨噬细胞（P < 0.05）。值得注意的是，全外显子测序（WES）数据分析显示，RCC 的突变频率显著高于 LCC（82,187/162 对 18,726/115，< 0.01）。单细胞分析确定了 RCC 中主要的肿瘤细胞亚群，其特征是增殖潜力增强和主要组织相容性复合体 I 类分子表达增加。然而，RCC 中的主要 CD8 + T 细胞亚群表现出高度分化的状态，其特征是 T 细胞耗竭和近期激活，定义为肿瘤特异性细胞毒性 T 淋巴细胞（CTL）。免疫荧光和流式细胞术结果证实了这一趋势。此外，细胞间通讯分析表明，RCC 中肿瘤特异性 CTL 与肿瘤细胞之间的相互作用数量更多、强度更大。
肿瘤微环境中存在大量肿瘤特异性细胞毒性 T 淋巴细胞（CTL）且肿瘤细胞免疫原性增加的 RCC 患者可能是免疫检查点抑制剂治疗的更好候选者。
