Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer.

Abstract

Immune checkpoint inhibitors (ICIs) have become a promising area of research for cancer treatment. In addition to the well-known ICIs targeting PD-1/PD-L1, HLA-G/ILT-2/-4 is relatively new immune checkpoint that has been evaluated in early clinical trials in patients with advanced solid tumors. In this study, the expression of HLA-G (n=157), ILT-2/4 (n=82), and PD-L1 (n=70) in epithelial cell adhesion molecule (EpCAM)-positive colorectal cancer (CRC) cells was analyzed by multicolor flow cytometry, and the prognostic significance of these molecules was evaluated. In EpCAM+ CRC cells, the median percentages of HLA-G, ILT-2, ILT-4, and PD-L1 were 14.90%, 67.70%, 8.55% and 80.30%, respectively. In addition, a positive correlation was observed between them (all p<0.001). Higher levels of these immune checkpoint proteins are associated with lymph node metastasis. In addition to the AJCC stage (p=0.001), Kaplan-Meier survival analysis showed that higher levels of HLA-G (p=0.041), ILT-2 (p=0.060), ILT-4 (p<0.001), PD-L1 (p=0.012), HLA-GILT4 (p<0.001) and ILT-2ILT-4 (p<0.001) were significantly associated with shorter survival of CRC patients. When CRC patients were stratified by early and advanced AJCC stages, HLA-G levels were only related to the survival among CRC patients with early disease stage (p=0.024), while ILT-4 levels were significant for both CRC patients with early (p=0.001) and advanced (p=0.020) disease stages. Multivariate cox regression analysis revealed that advanced AJCC stage (HR=2.435; p=0.005) and higher ILT-4 levels (HR=2.198; p=0.063) were independent risk factors for poor outcomes in patients with CRC. In summary, among the immune checkpoints, HLA-G/ILT-2/4 and PD-L1, ILT-4 is the most significant prognostic indicator of CRC. This finding indicated that a combination of immunotherapy strategies, such as ILT-4 blockade, could improve the clinical outcomes in patients with cancer. Moreover, multicolor flow cytometry can be employed as a reliable and efficient, alternative to immunohistochemistry, for evaluating the immune checkpoint proteins expressed in tumor lesions.

• Authors: Qiong-Yuan Chen, Yu-Xin Chen, Qiu-Yue Han, Jiang-Gang Zhang, Wen-Jun Zhou, Xia Zhang, Yao-Han Ye, Wei-Hua Yan, Aifen Lin
• Journal: Frontiers in immunology (Front Immunol) Vol. 12 Pg. 679090 ( 2021) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 34054869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Chen, Chen, Han, Zhang, Zhou, Zhang, Ye, Yan and Lin.

Chemical References

• Antigens, CD
• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• HLA-G Antigens
• Immune Checkpoint Proteins
• LILRB1 protein, human
• LILRB2 protein, human
• Leukocyte Immunoglobulin-like Receptor B1
• Membrane Glycoproteins
• Receptors, Immunologic

Topics

• Adult
• Aged
• Aged, 80 and over
• Antigens, CD (genetics, metabolism)
• B7-H1 Antigen (genetics, metabolism)
• Biomarkers, Tumor
• Colorectal Neoplasms (diagnosis, etiology, metabolism, mortality)
• Disease Susceptibility
• Female
• Gene Expression
• HLA-G Antigens (genetics, immunology)
• Humans
• Immune Checkpoint Proteins (genetics, metabolism)
• Immunophenotyping
• Kaplan-Meier Estimate
• Leukocyte Immunoglobulin-like Receptor B1 (genetics, metabolism)
• Male
• Membrane Glycoproteins (genetics, metabolism)
• Middle Aged
• Neoplasm Staging
• Prognosis
• Receptors, Immunologic (genetics, metabolism)