Accumulation of Tumor-Infiltrating CD49a+ NK Cells Correlates with Poor Prognosis for Human Hepatocellular Carcinoma

Accumulation of CD49a+ NK cells in human hepatocellular carcinoma (HCC) correlates with tumor growth and poor prognosis. This NK-cell subset may negatively regulate immune responses and promote the development of HCC. The discovery of CD49a+ liver-resident natural killer (NK) cells in mice alters our view of NK cells and provides another opportunity to study NK cells. Although evidence has suggested roles for NK cells in liver diseases, whether and how CD49a+ NK cells contribute to liver diseases remain unclear. In this study, we observed that accumulation of CD49a+ tissue-resident NK cells in human hepatocellular carcinoma (HCC) was higher than in peritumoral tissues. We studied the exhausted and regulatory phenotypes of CD49a+ tissue-resident NK cells by analysis of protein and mRNA. The proportion of CD49a+ NK cells was positively correlated to the proportion of NK cells expressing inhibitory receptors. In addition, CD49a+ NK cells expressed more of checkpoint molecules PD-1, CD96, and TIGIT. Transcriptomic analysis implicated CD49a+ tissue-resident NK cells in the negative regulation of immune responses. Comparison of murine and human CD49a+ NK cells revealed their distinct characteristics and functions. Finally, accumulation of tissue-resident CD49a+ NK cells in liver tumor was correlated to deteriorating disease condition and poor prognosis. Our findings show that CD49a+ NK cells accumulate in liver tumor and suggest a role for CD49a+ NK cells in the negative regulation of immune responses and the development of HCC.

[1]  Meijuan Huang,et al.  Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma , 2019, Hepatology.

[2]  K. Qu,et al.  Liver‐Resident NK Cells Control Antiviral Activity of Hepatic T Cells via the PD‐1‐PD‐L1 Axis , 2019, Immunity.

[3]  R. Sun,et al.  Tissue-resident lymphocytes: from adaptive to innate immunity , 2019, Cellular & Molecular Immunology.

[4]  Jiu-Yao Wang,et al.  Warm up, cool down, and tearing apart in NK cell memory , 2018, Cellular & Molecular Immunology.

[5]  R. V. van Lier,et al.  Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC , 2018, Front. Immunol..

[6]  A. Ashkar,et al.  Shining light on the significance of NK cell CD56 brightness , 2018, Cellular & Molecular Immunology.

[7]  Meijuan Huang,et al.  Reduced CD160 Expression Contributes to Impaired NK-cell Function and Poor Clinical Outcomes in Patients with HCC. , 2018, Cancer research.

[8]  D. Noonan,et al.  Natural Killer Cells from Malignant Pleural Effusion Are Endowed with a Decidual-Like Proangiogenic Polarization , 2018, Journal of immunology research.

[9]  S. Khakoo,et al.  IL‐12 and IL‐15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells , 2017, Immunity, inflammation and disease.

[10]  R. Sun,et al.  Liver-resident NK cells and their potential functions , 2017, Cellular & Molecular Immunology.

[11]  M. Altfeld,et al.  Proliferative capacity exhibited by human liver-resident CD49a+CD25+ NK cells , 2017, PloS one.

[12]  N. Waddell,et al.  Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells , 2017, Nature Immunology.

[13]  M. Colonna,et al.  SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling , 2017, Nature Immunology.

[14]  E. King,et al.  Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer , 2017, Nature Immunology.

[15]  Z. Tian,et al.  Diversity of tissue-resident NK cells. , 2017, Seminars in immunology.

[16]  E. Tartour,et al.  Induction of resident memory T cells enhances the efficacy of cancer vaccine , 2017, Nature Communications.

[17]  V. Male.  Liver-Resident NK Cells: The Human Factor. , 2017, Trends in immunology.

[18]  L. Folkersen,et al.  CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin , 2017, Immunity.

[19]  D. Speiser,et al.  Very Late Antigen-1 Marks Functional Tumor-Resident CD8 T Cells and Correlates with Survival of Melanoma Patients , 2016, Front. Immunol..

[20]  B. Davidson,et al.  Eomeshi NK Cells in Human Liver Are Long-Lived and Do Not Recirculate but Can Be Replenished from the Circulation , 2016, The Journal of Immunology.

[21]  W. Yin,et al.  Liver-infiltrating CD11b−CD27− NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression , 2016, Cellular and Molecular Immunology.

[22]  Joseph C. Sun,et al.  Transforming Growth Factor-β Signaling Guides the Differentiation of Innate Lymphoid Cells in Salivary Glands. , 2016, Immunity.

[23]  L. Tang,et al.  Differential phenotypic and functional properties of liver-resident NK cells and mucosal ILC1s. , 2016, Journal of autoimmunity.

[24]  L. Brossay,et al.  Phenotype and functions of conventional and non-conventional NK cells. , 2016, Current opinion in immunology.

[25]  C. Leslie,et al.  Cancer Immunosurveillance by Tissue-Resident Innate Lymphoid Cells and Innate-like T Cells , 2016, Cell.

[26]  E. Clambey,et al.  Tissue-Resident NK Cells Mediate Ischemic Kidney Injury and Are Not Depleted by Anti–Asialo-GM1 Antibody , 2015, The Journal of Immunology.

[27]  Yan Chen,et al.  Human fused NKG2D–IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells , 2015, Cellular and Molecular Immunology.

[28]  Z. Tian,et al.  Re-examining the origin and function of liver-resident NK cells. , 2015, Trends in immunology.

[29]  H. Ljunggren,et al.  Cutting Edge: Identification and Characterization of Human Intrahepatic CD49a+ NK Cells , 2015, The Journal of Immunology.

[30]  D. Kuang,et al.  B7-H1-expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets. , 2014, The Journal of clinical investigation.

[31]  M. Colonna,et al.  Cutting Edge: Salivary Gland NK Cells Develop Independently of Nfil3 in Steady-State , 2014, The Journal of Immunology.

[32]  Henrique Veiga-Fernandes,et al.  Differentiation of Type 1 ILCs from a Common Progenitor to All Helper-like Innate Lymphoid Cell Lineages , 2014, Cell.

[33]  Maxim N. Artyomov,et al.  Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells , 2014, eLife.

[34]  Z. Tian,et al.  Tissue-resident natural killer cells and their potential diversity. , 2014, Seminars in immunology.

[35]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[36]  Xiang Gao,et al.  Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. , 2013, The Journal of clinical investigation.

[37]  M. Bureau,et al.  Mucosal Imprinting of Vaccine-Induced CD8+ T Cells Is Crucial to Inhibit the Growth of Mucosal Tumors , 2013, Science Translational Medicine.

[38]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[39]  D. Topham,et al.  Identification of a Unique Population of Tissue-Memory CD4+ T Cells in the Airways after Influenza Infection That Is Dependent on the Integrin VLA-1 , 2010, The Journal of Immunology.

[40]  O. Boyman,et al.  α1β1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis , 2007, Nature Medicine.

[41]  H. El‐Serag,et al.  Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. , 2007, Gastroenterology.

[42]  Jonathan A. Rebhahn,et al.  Collagen Distribution and Expression of Collagen-Binding α1β1 (VLA-1) and α2β1 (VLA-2) Integrins on CD4 and CD8 T Cells during Influenza Infection1 , 2007, The Journal of Immunology.

[43]  C. Tayade,et al.  Differential transcription of Eomes and T‐bet during maturation of mouse uterine natural killer cells , 2005, Journal of leukocyte biology.

[44]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  P. Doherty,et al.  The Collagen Binding α1β1 Integrin VLA-1 Regulates CD8 T Cell-Mediated Immune Protection against Heterologous Influenza Infection , 2004 .

[46]  P. Hervé,et al.  Direct selection of human bone marrow mesenchymal stem cells using an anti‐CD49a antibody reveals their CD45med,low phenotype , 2003, British journal of haematology.

[47]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[48]  I. Bank,et al.  Functional role of VLA-1 (CD49A) in adhesion, cation-dependent spreading, and activation of cultured human T lymphocytes. , 1994, Cellular immunology.

[49]  C. Cabañas,et al.  Functional regulation of the human integrin VLA‐1 (CD49a/CD29) by divalent cations and stimulatory β1 antibodies , 1994, FEBS letters.

[50]  Jonathan A. Rebhahn,et al.  Collagen distribution and expression of collagen-binding alpha1beta1 (VLA-1) and alpha2beta1 (VLA-2) integrins on CD4 and CD8 T cells during influenza infection. , 2007, Journal of immunology.

[51]  O. Boyman,et al.  Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. , 2007, Nature medicine.

[52]  P. Doherty,et al.  The collagen binding alpha1beta1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection. , 2004, Immunity.