Tumor-Infiltrating Immune Cells Act as a Marker for Prognosis in Colorectal Cancer

Lele Ye; Teming Zhang; Zhengchun Kang; Gangqiang Guo; Yongji Sun; Kangming Lin; Qunjia Huang; Xinyu Shi; Zhonglin Ni; Ning Ding; Kong-Nan Zhao; Wenjun Chang; Junjie Wang; Feng Lin; Xiangyang Xue

doi:10.3389/fimmu.2019.02368

Tumor-Infiltrating Immune Cells Act as a Marker for Prognosis in Colorectal Cancer

Front Immunol. 2019 Oct 17:10:2368. doi: 10.3389/fimmu.2019.02368. eCollection 2019.

Authors

Lele Ye^{1

2}, Teming Zhang³, Zhengchun Kang⁴, Gangqiang Guo², Yongji Sun⁵, Kangming Lin², Qunjia Huang², Xinyu Shi², Zhonglin Ni⁶, Ning Ding², Kong-Nan Zhao², Wenjun Chang⁷, Junjie Wang⁸, Feng Lin⁹, Xiangyang Xue²

Affiliations

¹ Department of Gynecologic Oncology, Wenzhou Central Hospital, Wenzhou, China.
² Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China.
³ Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
⁴ Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
⁵ First Clinical College, Wenzhou Medical University, Wenzhou, China.
⁶ Department of General Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
⁷ Department of Environmental Health, Naval Medical University, Shanghai, China.
⁸ Department of Critical Care Medicine, Shanghai Tenth People's Hosptial, Tongji University School of Medicine, Shanghai, China.
⁹ Department of General Surgery, Taizhou First People's Hospital, Taizhou, China.

Abstract

Tumor-infiltrating immune cells (TIICs) play essential roles in cancer development and progression. However, the association of TIICs with prognosis in colorectal cancer (CRC) patients remains elusive. Infiltration of TIICs was assessed using ssGSEA and CIBERSORT tools. The association of TIICs with prognosis was analyzed in 1,802 CRC data downloaded from the GEO (https://www.ncbi.nlm.nih.gov/geo/) and TCGA (https://portal.gdc.cancer.gov/) databases. Three populations of TIICs, including CD66b+ tumor-associated neutrophils (TANs), FoxP3+ Tregs, and CD163+ tumor-associated macrophages (TAMs) were selected for immunohistochemistry (IHC) validation analysis in 1,008 CRC biopsies, and their influence on clinical features and prognosis of CRC patients was analyzed. Prognostic models were constructed based on the training cohort (359 patients). The models were further tested and verified in testing (249 patients) and validation cohorts (400 patients). Based on ssGSEA and CIBERSORT analysis, the correlation between TIICs and CRC prognosis was inconsistent in different datasets. Moreover, the results with disease-free survival (DFS) and overall survival (OS) data in the same dataset also differed. The high abundance of TIICs found by ssGSEA or CIBERSORT tools can be used for prognostic evaluation effectively. IHC results showed that TANs, Tregs, TAMs were significantly correlated with prognosis in CRC patients and were independent prognostic factors (P_DFS ≤ 0.001; P_OS ≤ 0.023). The prognostic predictive models were constructed based on the numbers of TANs, Tregs, TAMs (C-index_DFS&OS = 0.86; AIC_DFS = 448.43; AIC_OS = 184.30) and they were more reliable than traditional indicators for evaluating prognosis in CRC patients. Besides, TIICs may affect the response to chemotherapy. In conclusion, TIICs were correlated with clinical features and prognosis in patients with CRC and thus can be used as markers.

Keywords: TAMs; TANs; TIICs; Tregs; chemotherapy; colorectal cancer; prognosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms* / diagnosis
Colorectal Neoplasms* / immunology
Colorectal Neoplasms* / pathology
Databases, Factual*
Female
Humans
Immunohistochemistry
Lymphocytes, Tumor-Infiltrating* / immunology
Lymphocytes, Tumor-Infiltrating* / pathology
Macrophages* / immunology
Macrophages* / pathology
Male
Models, Immunological*
Neutrophils* / immunology
Neutrophils* / pathology
Prognosis
T-Lymphocytes, Regulatory* / immunology
T-Lymphocytes, Regulatory* / pathology