The Expression of ILT4 in Myeloid Dendritic Cells in Patients with Hepatocellular Carcinoma

ABSTRACT Immunoglobulin-like transcript (ILT) 4 is an inhibitory immune receptor of the immunoglobulin superfamily, which could deliver inhibitory signals and induce immunosuppression. The significance of the expression of ILT4 in mDCs subsets in patients with hepatocellular carcinoma (HCC) remains unclear. In this study, the frequency of mDCs subsets in the peripheral blood of 121 patients with HCC and 103 normal controls, and in the tumor and tumor free liver tissues (TFL) of 43 HCC patients was analyzed by flow cytometry. Then, the expressions of ILT4 in mDCs subsets in the microenvironment of liver cancer were also analyzed. Results showed that the percentage of CD1c+ subset was dramatically decreased in peripheral blood mononuclear cells (PBMCs) of HCC patients compared with normal controls, and also significantly decreased in tumor tissue compared with the TFL. The decreased of CD1c+ subset in blood could be a diagnostic factor for HCC with the area under the receiver operating characteristic curve 0.975 (P < 0.01). The percentage of ILT4+CD1c+ subset was dramatically increased in tumor than that of TFL and blood. There were significant correlations between the percentage of ILT4+ in CD1c+ subset in tumor and that of in blood. The percentage of ILT4+CD1c+ subset in tumor tissue was strongly associated with the Edmondson-Steiner stage in HCC (P = 0.03). Furthermore, the capacity of ILT4+CD1c+ subset producing IFN-γ was lower than ILT4− CD1c subset in PBMC of HCC patients following Poly I:C stimulation. Taken together, the increased ILT4+CD1c+ subset in tumor tissue might play an important role in immune suppression for patients with HCC.

[1]  B. Kong,et al.  Dendritic cells as cancer therapeutics. , 2019, Seminars in cell & developmental biology.

[2]  S. Abd-Elsalam,et al.  High numbers of myeloid derived suppressor cells in peripheral blood and ascitic fluid of cirrhotic and HCC patients , 2018, Immunological investigations.

[3]  M. Heikenwalder,et al.  The immunology of hepatocellular carcinoma , 2018, Nature Immunology.

[4]  C. Slingluff,et al.  Immunotherapy for hepatocellular carcinoma patients: is it ready for prime time? , 2018, Cancer Immunology, Immunotherapy.

[5]  S. Ferrone,et al.  Immunomodulating and Immunoresistance Properties of Cancer-Initiating Cells: Implications for the Clinical Success of Immunotherapy , 2017, Immunological investigations.

[6]  Zhuoli Zhang,et al.  Dendritic cells based immunotherapy. , 2017, American journal of cancer research.

[7]  Adam C. Gower,et al.  TLR3 Signaling Promotes the Induction of Unique Human BDCA-3 Dendritic Cell Populations , 2016, Front. Immunol..

[8]  J. Prieto,et al.  Immunological landscape and immunotherapy of hepatocellular carcinoma , 2015, Nature Reviews Gastroenterology &Hepatology.

[9]  Zhigang Lu,et al.  Inhibitory leukocyte immunoglobulin-like receptors in cancer development , 2015, Science China Life Sciences.

[10]  Meredith O'Keeffe,et al.  Human dendritic cell subsets and function in health and disease , 2015, Cellular and Molecular Life Sciences.

[11]  M. Samson,et al.  Biology of the immunomodulatory molecule HLA-G in human liver diseases. , 2015, Journal of hepatology.

[12]  P. Sharma,et al.  Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential , 2015, Cell.

[13]  Florent Ginhoux,et al.  Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny , 2014, Nature Reviews Immunology.

[14]  J. Geoghegan,et al.  CD141⁺ myeloid dendritic cells are enriched in healthy human liver. , 2014, Journal of hepatology.

[15]  B. Diamond,et al.  Transcriptional and functional profiling of human intestinal dendritic cells reveals conserved specialization and a role for Bcl-6 and Blimp-1 in terminal subset differentiation , 2013, Nature Immunology.

[16]  C. Scheibenbogen,et al.  Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses. , 2013, Blood.

[17]  I. Mellman,et al.  Oncology meets immunology: the cancer-immunity cycle. , 2013, Immunity.

[18]  F. Nestle,et al.  Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation , 2012, The Journal of experimental medicine.

[19]  R. Salter,et al.  Dendritic cells in cancer , 2009 .

[20]  Wei Zhang,et al.  Mechanisms of prolongation of allograft survival by HLA-G/ILT4-modified dendritic cells. , 2007, Human immunology.

[21]  J. Trowsdale,et al.  The LILR family: modulators of innate and adaptive immune pathways in health and disease. , 2004, Tissue antigens.

[22]  Li Wu,et al.  Development of dendritic cell system. , 2004, Cellular & molecular immunology.

[23]  Kouhei Tsumoto,et al.  Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D. Mancini,et al.  High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. , 2003, Transplant immunology.

[25]  Yong‐jun Liu,et al.  Mouse and human dendritic cell subtypes , 2002, Nature Reviews Immunology.

[26]  M. Colonna,et al.  A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. , 2000, Seminars in immunology.

[27]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[28]  Y. Becker,et al.  Characterization of human blood dendritic cells: cytokine profiles. , 1995, Advances in experimental medicine and biology.

[29]  R. Steinman,et al.  The dendritic cell system and its role in immunogenicity. , 1991, Annual review of immunology.

[30]  D. Woodfield Hepatocellular carcinoma. , 1986, The New Zealand medical journal.