Multi-omics analysis reveals the landscape of tumor microenvironments in left-sided and right-sided colon cancer

Dongfang Liu; Chen Li; Zenghua Deng; Nan Luo; Wenxia Li; Wenzhe Hu; Xiang Li; Zichao Qiu; Jianfei Chen; Jirun Peng

doi:10.3389/fmed.2024.1403171

Multi-omics analysis reveals the landscape of tumor microenvironments in left-sided and right-sided colon cancer

Front Med (Lausanne). 2024 Aug 29:11:1403171. doi: 10.3389/fmed.2024.1403171. eCollection 2024.

Authors

Dongfang Liu^#¹, Chen Li^#¹, Zenghua Deng¹, Nan Luo¹, Wenxia Li¹, Wenzhe Hu¹, Xiang Li¹, Zichao Qiu¹, Jianfei Chen¹, Jirun Peng^{1

2}

Affiliations

¹ Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
² Ninth School of Clinical Medicine, Peking University, Beijing, China.

^# Contributed equally.

Abstract

Background: 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.

Methods: 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).

Result: 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, P < 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.

Conclusion: 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.

Keywords: PD-1; TME; colorectal cancer; immune therapy; left-sided colon cancer; right-sided colon cancer.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of the article. This work was supported by grants from the National Natural Science Foundation of China (nos. 91742203, 82072601, and 82372796).