Purpose:HLA-G binds to the inhibitory receptors of uterine NK cells and plays an
important role in protection of fetal cells from maternal NK lysis. HLA-G also
mediates tumor escape, but the immunosuppressive role is often neglected. These
studies have focused on the examination of HLA-G expression in human breast and
ovarian carcinoma and HLA-G immunosuppressive role in NK cytolysis. Methods: We examined HLA-G
expression in breast and ovarian carcinoma cell lines by real time PCR, ELISA
and immunofluorescent staining, and in frozen breast and ovarian carcinoma
tissues by immunohistochemistry (IHC). We treated the breast cancer cell lines
with anti-human HLA-G antibody or progesterone. Then, NK cytolysis was measured
by using MTT assay. Results: We find breast and ovarian cancer cell lines increase the expression of
HLA-G mRNA and protein, compared to normal cells. IHC shows that 100% of frozen
breast and ovarian carcinoma tissues overexpress HLA-G protein. HLA-G IHC
scores of breast and ovarian carcinoma are significantly higher than normal
breast and ovarian tissues, respectively (both p < 0.01). Blocking HLA-G of
the breast cancer cells by the antibody increases NK cytolysis. Progesterone
upregulates HLA-G mRNA and protein of human breast cancer cell lines. The increased
HLA-G expression by progesterone suppresses the NK cytolysis.Conclusion: Human breast and
ovarian carcinoma overexpress HLA-G immunosuppressive molecules. Blocking HLA-G
protein by antibody improves the cytolysis of NK cells against human breast cancer
cell lines. In contrast, upregulation of HLA-G expression by progesterone
impairs NK cytolytic function. Thus, HLA-G is a new immune checkpoint protein
and potential cancer immunotherapeutic target.
References
[1]
Kelly, A. and Trowsdale, J. (2019) Genetics of Antigen Processing and Presentation. Immunogenetics, 71, 161-170. https://doi.org/10.1007/s00251-018-1082-2
[2]
Campoli, M. and Ferrone, S. (2008) HLA Antigen Changes in Malignant Cells: Epigenetic Mechanisms and Biologic Significance. Oncogene, 27, 5869-5885.
https://doi.org/10.1038/onc.2008.273
[3]
Chang, C.C., Campoli, M. and Ferrone, S. (2005) Classical and Nonclassical HLA Class I Antigen and NK Cell-Activating Ligand Changes in Malignant Cells: Current Challenges and Future Directions. Advances in Cancer Research, 93, 189-234.
https://doi.org/10.1016/S0065-230X(05)93006-6
[4]
Algarra, I., Collado, A. and Garrido, F. (1997) Altered MHC Class I Antigens in Tumors. International Journal of Clinical and Laboratory Research, 27, 95-102.
https://doi.org/10.1007/BF02912442
[5]
Garrido, F., Ruiz-Cabello, F., Cabrera, T., Pérez-Villar, J.J., López-Botet, M., Duggan-Keen, M. and Stern, P.L. (1997) Implications for Immunosurveillance of Altered HLA Class I Phenotypes in Human Tumours. Trends in Immunology, 18, 89-95. https://doi.org/10.1016/S0167-5699(96)10075-X
[6]
Koopman, L.A., Corver, W.E., van der Slik, A.R., Giphart, M.J. and Fleuren, G.J. (2000) Multiple Genetic Alterations Cause Frequent and Heterogeneous Human Histocompatibility Leukocyte Antigen Class I Loss in Cervical Cancer. Journal of Experimental Medicine, 191, 961-976. https://doi.org/10.1084/jem.191.6.961
[7]
Carosella, E.D., Rouas-Freiss, N., Tronik-Le Roux, D., Moreau, P. and LeMaoult, J. (2015) HLA-G: An Immune Checkpoint Molecule. Advances in Immunology, 127, 133-144. https://doi.org/10.1016/bs.ai.2015.04.001
[8]
Garziera, M. and Toffoli, G. (2014) Inhibition of Host Immune Response in Colorectal Cancer: Human Leukocyte Antigen-G and Beyond. World Journal of Gastroenterology, 20, 3778-3794. https://doi.org/10.3748/wjg.v20.i14.3778
[9]
Gonen-Gross, T., Goldman-Wohl, D., Huppertz, B., Lankry, D., Greenfield, C., Natanson-Yaron, S., et al. (2010) Inhibitory NK Receptor Recognition of HLA-G: Regulation by Contact Residues and by Cell Specific Expression at the Fetal-Maternal Interface. PLOS ONE, 5, Article ID: e8941.
https://doi.org/10.1371/journal.pone.0008941
[10]
Le Discorde, M., Moreau, P., Sabatier, P., Legeais, J.M. and Carosella, E.D. (2003) Expression of HLA-G in Human Cornea, an Immune-Privileged Tissue. Human Immunology, 64, 1039-1044. https://doi.org/10.1016/j.humimm.2003.08.346
[11]
Crisa, L., McMaster, M.T., Ishii, J.K., Fisher, S.J. and Salomon, D.R. (1997) Identification of a Thymic Epithelial Cell Subset Sharing Expression of the Class Ib HLA-G Molecule with Fetal Trophoblasts. Journal of Experimental Medicine, 186, 289-298.
https://doi.org/10.1084/jem.186.2.289
[12]
Cirulli V1, Zalatan, J., McMaster, M., Prinsen, R., Salomon, D.R., Ricordi, C., Torbett, B.E., Meda, P. and Crisa, L. (2006) The Class I HLA Repertoire of Pancreatic Islets Comprises the Nonclassical Class Ib Antigen HLA-G. Diabetes, 55, 1214-1222.
https://doi.org/10.2337/db05-0731
[13]
Lin, A. and Yan, W.H. (2015) Human Leukocyte Antigen-G (HLA-G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy. Molecular Medicine, 21, 782-791. https://doi.org/10.2119/molmed.2015.00083
[14]
Rizzo, R., Bortolotti, D., Baricordi, O.R. and Fainardi, E. (2012) New Insights into HLA-G and Inflammatory Diseases. Inflammation & Allergy—Drug Targets, 11, 448-463. https://doi.org/10.2174/187152812803590037
[15]
Laaribi, A.B., Bortolotti, D., Hannachi, N., Mehri, A., Hazgui, O., Ben Yahia, H., et al. (2017) Increased Levels of Soluble HLA-G Molecules in Tunisian Patients with Chronic Hepatitis B Infection. Journal of Viral Hepatitis, 24, 1016-1022.
https://doi.org/10.1111/jvh.12718
[16]
Urosevic, M. and Dummer, R. (2008) Human Leukocyte Antigen-G and Cancer Immunoediting. Cancer Research, 68, 627-630.
https://doi.org/10.1158/0008-5472.CAN-07-2704
[17]
Carosella, E., Favier, B., Rouas-Freiss, N., Moreau, P. and Lemaoult, J. (2008) Beyond the Increasing Complexity of the Immunomodulatory HLA-G Molecule. Blood, 111, 4862-4870. https://doi.org/10.1182/blood-2007-12-127662
[18]
Amodio, G., Sales de Albuquerque, R. and Gregori, S. (2014) New Insights into HLA-G Mediated Tolerance. Tissue Antigens, 84, 255-263.
https://doi.org/10.1111/tan.12427
[19]
Yie, S.M., Li, L.H., Li, G.M., Xiao, R. and Librach, C.L. (2006) Progesterone Enhances HLA-G Gene Expression in JEG-3 Choriocarcinoma Cells and Human Cytotrophoblasts in Vitro. Human Reproduction, 21, 46-51.
https://doi.org/10.1093/humrep/dei305
[20]
Yie, S.M., Xiao, R. and Librach, C.L. (2006) Progesterone Regulates HLA-G Gene Expression through a Novel Progesterone Response Element. Human Reproduction, 21, 2538-2544. https://doi.org/10.1093/humrep/del126
[21]
Castelli, C.C., Veiga-Castelli, L.C., Yaghi, L., Moreau, P. and Donadi, E.A. (2014) Transcriptional and Posttranscriptional Regulations of the HLA-G Gene. Journal of Immunology Research, 2014, Article ID: 734068.
https://doi.org/10.1155/2014/734068
[22]
Stites, D.P., Bugbee, S. and Siiteri, P.K. (1983) Differential Actions of Progesterone and Cortisol on Lymphocyte and Monocyte Interaction during Lymphocyte Activation—Relevance to Immunosuppression in Pregnancy. Journal of Reproductive Immunology, 5, 215-228. https://doi.org/10.1016/0165-0378(83)90237-1
[23]
Elliott, R.L. (2016) Cancer Immunotherapy “HLA-G an Important Neglected Immunosuppressive Molecule”. SOJ Immunology, 4, 1-3.
https://doi.org/10.15226/2372-0948/4/1/00146
[24]
Tam, Y.K., Maki, G., Miyagawa, B., Hennemann, B., Tonn, T. and Klingemann, H.G. (1999) Characterization of Genetically Altered, Interleukin, 2-Independent Natural Killer Cell Lines Suitable for Adoptive Cell Immunotherapy. Human Gene Therapy, 10, 1359-1373. https://doi.org/10.1089/10430349950018030
[25]
Jiang, X.P., Elliott, R.L. and Head, J.F. (2015) Exogenous Normal Mammary Epithelial Mitochondria Suppress Glycolytic Metabolism and Glucose Uptake of Human Breast Cancer Cells. Breast Cancer Research and Treatment, 153, 519-529.
https://doi.org/10.1007/s10549-015-3583-0
[26]
Klein, M., Vignaud, J.M., Hennequin, V., Toussaint, B., Bresler, L., Plénat, F., Leclère, J., Duprez, A. and Weryha, G. (2001) Increased Expression of the Vascular Endothelial Growth Factor Is a Pejorative Prognosis Marker in Papillary Thyroid Carcinoma. The Journal of Clinical Endocrinology & Metabolism, 86, 656-658.
https://doi.org/10.1210/jcem.86.2.7226
[27]
Fedchenko, N. and Reifenrath, J. (2014) Different Approaches for Interpretation and Reporting of Immunohistochemistry Analysis Results in the Bone Tissue—A Review. Diagnostic Pathology, 9, Article No. 221.
https://doi.org/10.1186/s13000-014-0221-9
[28]
Jiang, X.P. and Elliott, R.L. (2017) Decreased Iron in Cancer Cells and Their Microenvironment Improves Cytolysis of Breast Cancer Cells by Natural Killer Cells. Anticancer Research, 37, 2297-2305. https://doi.org/10.21873/anticanres.11567
[29]
Attardi, B.J., Zeleznik, A., Simhan, H., Chiao, J.P., Mattison, D.R. and Caritis, S.N. (2007) Comparison of Progesterone and Glucocorticoid Receptor Binding and Stimulation of Gene Expression by Progesterone, 17-Alpha Hydroxyprogesterone Caproate (17-OHPC), and Related Progestins. American Journal of Obstetrics and Gynecology, 197, 599.e1-599.e7. https://doi.org/10.1016/j.ajog.2007.05.024
[30]
Rouas-Freiss, N., LeMaoult, J., Verine, J., Roux, D.T., Culine, S. and Hennequin, C. (2017) Intratumor Heterogeneity of Immune Checkpoints in Primary Renal Cell Cancer: Focus on HLA-G/ILT2/ILT4. OncoImmunology, 6, Article ID: e1342023.
https://doi.org/10.1080/2162402X.2017.1342023
[31]
Sharma, P., Wagner, K., Wolchok, J.D. and Allison, J.P. (2011) Novel Cancer Immunotherapy Agents with Survival Benefit: Recent Successes and Next Steps. Nature Reviews Cancer, 11, 805-812. https://doi.org/10.1038/nrc3153
[32]
Wolchok, J.D. and Chan, T.A. (2014) Cancer: Antitumour Immunity Gets a Boost. Nature, 515, 496-498. https://doi.org/10.1038/515496a
[33]
Herbst, R.S., Soria, J.C., Kowanetz, M., Fine, G.D., Hamid, O., Gordon, M.S., et al. (2014) Predictive Correlates of Response to the Anti-PD-L1 Antibody MPDL3280A in Cancer Patients. Nature, 515, 563-567. https://doi.org/10.1038/nature14011
[34]
Choueiri, T.K., Figueroa, D.J., Fay, A.P., Signoretti, S., Liu, Y., Gagnon, R., Deen, K., Carpenter, C., Benson, P., Ho, T.H., et al. (2015) Correlation of PD-L1 Tumor Expression and Treatment Outcomes in Patients with Renal Cell Carcinoma Receiving Sunitinib or Pazopanib: Results from COMPARZ, a Randomized Controlled Trial. Clinical Cancer Research, 21, 1071-1077.
https://doi.org/10.1158/1078-0432.CCR-14-1993
[35]
Loumagne, L., Baudhuin, J., Favier, B., Montespan, F., Carosella, E.D. and Rouas-Freiss, N. (2014) In Vivo Evidence That Secretion of HLA-G by Immunogenic Tumor Cells Allows Their Evasion from Immunosurveillance. International Journal of Cancer, 135, 2107-2117. https://doi.org/10.1002/ijc.28845
[36]
Trabert, B., Bauer, D.C., Buist DSM, Cauley, J.A., Falk, R.T., Geczik, A.M., et al. (2020) Association of Circulating Progesterone with Breast Cancer Risk among Postmenopausal Women. JAMA Network Open, 3, Article ID: e203645.
https://doi.org/10.1001/jamanetworkopen.2020.3645
[37]
Prior, J.C. (2018) Progesterone for Treatment of Symptomatic Menopausal Women. Climacteric, 21, 358-365. https://doi.org/10.1080/13697137.2018.1472567
[38]
Deli, T., Orosz, M. and Jakab, A. (2020) Hormone Replacement Therapy in Cancer Survivors—Review of the Literature. Pathology & Oncology Research, 26, 63-78.
https://doi.org/10.1007/s12253-018-00569-x
[39]
Sivori, S., Vacca, P., Zotto, G.D., Munari, E., Mingari, M.C. and Moretta, L. (2019) Human NK Cells: Surface Receptors, Inhibitory Checkpoints, and Translational Applications. Cellular & Molecular Immunology, 16, 430-441.
https://doi.org/10.1038/s41423-019-0206-4
[40]
Mandelboim, O., Pazmany, L., Davis, D.M., Valés-Gómez, M., Reyburn, H.T., Rybalov, B.J.L. and Strominger, J.L. (1997) Multiple Receptors for HLA-G on Human Natural Killer Cells. Proceedings of the National Academy of Sciences of the United States of America, 94, 14666-14670. https://doi.org/10.1073/pnas.94.26.14666
[41]
Villa-álvarez, M., Sordo-Bahamonde, C., Lorenzo-Herrero, S., Gonzalez-Rodriguez, A.P., Payer, A.R., Gonzalez-Garcia, E., et al. (2018) Ig-Like Transcript, 2 (ILT2) Blockade and Lenalidomide Restore NK Cell Function in Chronic Lymphocytic Leukemia. Frontiers in Immunology, 9, Article No. 2917.
https://doi.org/10.3389/fimmu.2018.02917
