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ABSTRACT
Tumor-infiltrating lymphocytes (TILs) are vital elements of the tumor microenvironment (TME), and the anti-tumor activity of TILs on colorectal cancer (CRC) has been a topic of concern. However, the characteristics and prognosis of the various types of lymphocyte infiltration in CRC have not been fully explained. Our study aimed to identify distinct features and prognosis of TILs. We integrated multiple-cohort databases to illustrate the features, proportions, and prognosis of TILs on CRC. We found that macrophages were significantly enriched in CRC. When we used the scRNA-seq database to further evaluate the proportion of TILs, we noticed markedly higher numbers of CD4 + T cell, B cell, and CD8 + T cell in four Gene Expression Omnibus Series (GSE) CRC cohorts. Interestingly, we found that the infiltrating level of TIL subgroups from highest to lowest is always dendritic cells, CD8 + T cells, CD4 + T cells, neutrophils, B cells, and macrophages; the proportion of infiltration is largely constant regardless of mutations in specific genes or somatic copy number variation (sCNV). In addition, the data corroborated that CD4+ TILs and CD8+ TILs have certain application values in the prognosis of CRCs, and age negatively related to CD8+ TILs and B plasma infiltration. Finally, patients with CRC who are older than 70 years have a better response to immune-checkpoint blockade.
Graphic Abstract
Highlights
● The infiltrating level of TIL subgroups in CRC has a constant proportion.
● CD4+ TILs and CD8+ TILs present a better prognosis for CRC.
● Age is negatively related to CD8+TILs, which may demonstrate a worse prognosis.
● Age may be a vital factor in immunotherapy of patients with CRC.
● Patients older than 70 years respond better to ICB.
Acknowledgements
The authors would like to acknowledge the platforms TIMER 2.0, TISCH, CRI iAtlas Portal, ASSISTANT FOR Clinical Bioinformatics and Xiantao Academic for downloading and analyzing and acquiring clinical data of TCGA or GSE cohorts of CRC. The authors would also like to acknowledge the platforms HOME for Researchers, Fig Draw, TCGA, GSE, X-CELL, CIBERSORT, CIBERSORT-ABS, QUANTSEQ, EPIC, and Taylor & Francis Editing Services.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author Contributions
Conceptualization – Hulai Wei and Guangxian Xu; data curation – Miao Qin; formal analysis – Gang Chen and Jinxia Hou; founding acquisition – Bei Xie and Jing Chen; Methodology – Qun-Feng Wang, Li Wang an Li-na Wang; project administration – Dan Jiang and Ye Hu; writing – original draft-Miao Qin; writing – review & editing: Miao Qin, Hulai Wei and Guangxian Xu.
Availability of data and materials
The datasets analyzed for this study were obtained from the TIMER 2.0 (http://timer.cistrome.org), the TISCH (http://tisch.comp-genomics.org/home), and the GSE sc-seq samples (Zhang L, et al. Nature 2018; Wu TD, et al. Nature 2020; Zhang L, et al. Cell 2020), and the TCGA (https://portal.gdc.cancer.gov/).
Consent for publication
The manuscript is approved by all authors for publication.
Supplementary Material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/21655979.2022.2162660
Abbreviations
CRC: Colorectal cancer; COAD: Colon cancer; READ: Rectum cancer; TILs: Tumor-infiltrating lymphocytes; scRNA-seq: Single-cell RNA-sequence; ACT: Adoptive cell therapies; TCGA: The Cancer Genome Atlas; GEO: Gene Expression Omnibus; GSE: Gene Expression Omnibus Series; TNM: Tumor Lymph Node Metastasis; TIMER: Tumor Immune Estimation Resource; TISCH: The Cancer Immune Single-Cell Hub; Treg: Regulatory T cells; OS: Overall survival; TP53: Tumor Protein P53; APC: APC Regulator Of WNT Signaling Pathway; PIK3CA: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha; KRAS: Oncogene KRAS2; SCNA: Somatic copy number variation; TIMER: Tumor Immune Estimation Resource; X-Cell: Cell types enrichment analysis; quanTIseq: QUANTISEQ R package; MCP-counter: MCP-counter R package; MDSC: Myeloid-derived suppressor cells; CR: Complete response; TIDE: Tumor Immune Dysfunction and Exclusion; TME: Tumor microenvironment; ICB: Immune-checkpoint blockade; SKCM: Skin cutaneous melanoma; GBM: Glioblastoma; FOXP3: Forkhead Box P3; TNN: Tenascin N; CTLA-4: Cytotoxic T-Lymphocyte Associated Protein 4; LAG3: Lymphocyte Activating 3; PD-L2/PDCD1LG2: Programmed Cell Death 1 Ligand 2; SIGLEC15: Sialic Acid Binding Ig Like Lectin 15; HAVCR2: Hepatitis A Virus Cellular Receptor 2, TIM-3; PDCD1: Programmed Cell Death 1, PD-1; TIGIT: T Cell Immunoreceptor With Ig And ITIM Domains.