{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:08:15Z","timestamp":1791497295108,"version":"4.3.4"},"reference-count":144,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T00:00:00Z","timestamp":1583452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["23095"],"award-info":[{"award-number":["23095"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["2017CBNCYT"],"award-info":[{"award-number":["2017CBNCYT"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["#D15D18000410001"],"award-info":[{"award-number":["#D15D18000410001"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["grant agreeement 813284"],"award-info":[{"award-number":["grant agreeement 813284"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8+ cytotoxic and CD4+ activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell\u2013cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)\/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications.<\/jats:p>","DOI":"10.3390\/ijms21051825","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T09:26:41Z","timestamp":1583486801000},"page":"1825","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":147,"title":["Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions"],"prefix":"10.3390","volume":"21","author":[{"given":"Francesca","family":"Arruga","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, University of Turin, via Nizza, 52, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin Baffour","family":"Gyau","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, via Nizza, 52, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8940-1406","authenticated-orcid":false,"given":"Andrea","family":"Iannello","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, via Nizza, 52, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Vitale","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, via Nizza, 52, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Vaisitti","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, via Nizza, 52, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0632-5036","authenticated-orcid":false,"given":"Silvia","family":"Deaglio","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, via Nizza, 52, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1056\/NEJMra041720","article-title":"Chronic lymphocytic leukemia","volume":"352","author":"Chiorazzi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1182\/blood-2017-10-764373","article-title":"Chronic lymphocytic leukemia and mantle cell lymphoma: Crossroads of genetic and microenvironment interactions","volume":"131","author":"Puente","year":"2018","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1200\/JCO.2012.43.4449","article-title":"Overall and cancer-specific survival of patients with breast, colon, kidney, and lung cancers with and without chronic lymphocytic leukemia: A SEER population-based study","volume":"31","author":"Solomon","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.blre.2018.04.007","article-title":"Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies","volume":"32","author":"Teh","year":"2018","journal-title":"Blood Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/107327481502204s02","article-title":"Chronic Lymphocytic Leukemia in the Elderly: Epidemiology and Proposed Patient-Related Approach","volume":"22","author":"Balducci","year":"2015","journal-title":"Cancer Control"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1365-2141.2005.05789.x","article-title":"Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab*","volume":"132","author":"Thursky","year":"2006","journal-title":"Br. J. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.beha.2009.12.004","article-title":"Infectious complications of chronic lymphocytic leukaemia: Pathogenesis, spectrum of infection, preventive approaches","volume":"23","author":"Morrison","year":"2010","journal-title":"Best Pract. Res. Clin. Haematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1182\/blood-2015-03-567388","article-title":"Perturbation of the normal immune system in patients with CLL","volume":"126","author":"Forconi","year":"2015","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fattizzo, B., and Barcellini, W. (2020). Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01435"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1182\/blood.V96.8.2655","article-title":"Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1","volume":"96","author":"Burger","year":"2000","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1182\/blood.V99.3.1030","article-title":"Distinctive features of \u201cnurselike\u201d cells that differentiate in the context of chronic lymphocytic leukemia","volume":"99","author":"Tsukada","year":"2002","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.3324\/haematol.2012.073080","article-title":"The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation","volume":"98","author":"Maffei","year":"2013","journal-title":"Haematologica"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.bcmd.2012.12.003","article-title":"Circulating microenvironment of CLL: Are nurse-like cells related to tumor-associated macrophages?","volume":"50","author":"Filip","year":"2013","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"719","DOI":"10.4049\/jimmunol.1402272","article-title":"Chronic lymphocytic leukemia: A paradigm of innate immune cross-tolerance","volume":"194","author":"Cordoba","year":"2015","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1182\/blood-2004-03-0889","article-title":"Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha","volume":"106","author":"Nishio","year":"2005","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1182\/blood-2004-10-3873","article-title":"CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival","volume":"105","author":"Deaglio","year":"2005","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1038\/leu.2011.88","article-title":"A novel role of the CX3CR1\/CX3CL1 system in the cross-talk between chronic lymphocytic leukemia cells and tumor microenvironment","volume":"25","author":"Ferretti","year":"2011","journal-title":"Leukemia"},{"key":"ref_18","first-page":"4497","article-title":"The circulating dendritic cell compartment in patients with chronic lymphocytic leukemia is severely defective and unable to stimulate an effective T-cell response","volume":"63","author":"Orsini","year":"2003","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"46301","DOI":"10.18632\/oncotarget.10093","article-title":"Deregulation of SOCS5 suppresses dendritic cell function in chronic lymphocytic leukemia","volume":"7","author":"Toniolo","year":"2016","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1111\/j.1365-2141.2011.08902.x","article-title":"Association of an increased frequency of CD14+ HLA-DR lo\/neg monocytes with decreased time to progression in chronic lymphocytic leukaemia (CLL)","volume":"156","author":"Gustafson","year":"2012","journal-title":"Br. J. Haematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1182\/blood-2013-12-546416","article-title":"CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs","volume":"124","author":"Jitschin","year":"2014","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Huergo-Zapico, L., Acebes-Huerta, A., Gonzalez-Rodriguez, A.P., Contesti, J., Gonzalez-Garcia, E., Payer, A.R., Villa-Alvarez, M., Fernandez-Guizan, A., Lopez-Soto, A., and Gonzalez, S. (2014). Expansion of NK cells and reduction of NKG2D expression in chronic lymphocytic leukemia. Correlation with progressive disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108326"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e1330235","DOI":"10.1080\/2162402X.2017.1330235","article-title":"NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors","volume":"6","author":"MacFarlane","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"84889","DOI":"10.18632\/oncotarget.20031","article-title":"Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects","volume":"8","author":"Manukyan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/0165-2478(87)90110-6","article-title":"C1 and C4 abnormalities in chronic lymphocytic leukaemia and their significance","volume":"14","author":"Fust","year":"1987","journal-title":"Immunol. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/leu.2012.165","article-title":"Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function","volume":"27","author":"DiLillo","year":"2013","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1111\/j.1365-2141.2008.07050.x","article-title":"Early stage chronic lymphocytic leukaemia carrying unmutated IGHV genes is at risk of recurrent infections during watch and wait","volume":"141","author":"Rossi","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1038\/leu.2016.362","article-title":"Restrictions in the T-cell repertoire of chronic lymphocytic leukemia: High-throughput immunoprofiling supports selection by shared antigenic elements","volume":"31","author":"Vardi","year":"2017","journal-title":"Leukemia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1053\/j.seminhematol.2014.05.006","article-title":"Immunomodulation and immune reconstitution in chronic lymphocytic leukemia","volume":"51","author":"Riches","year":"2014","journal-title":"Semin. Hematol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1182\/blood-2012-09-457531","article-title":"T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production","volume":"121","author":"Riches","year":"2013","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1016\/j.celrep.2016.05.061","article-title":"Human Cytotoxic T Lymphocytes Form Dysfunctional Immune Synapses with B Cells Characterized by Non-Polarized Lytic Granule Release","volume":"15","author":"Kabanova","year":"2016","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nri3405","article-title":"Molecular mechanisms of T cell co-stimulation and co-inhibition","volume":"13","author":"Chen","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.immuni.2009.04.010","article-title":"Mechanisms of foxp3+ T regulatory cell-mediated suppression","volume":"30","author":"Shevach","year":"2009","journal-title":"Immunity"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2012053","DOI":"10.4084\/mjhid.2012.053","article-title":"Regulatory T-cells in chronic lymphocytic leukemia and autoimmune diseases","volume":"4","author":"Rossi","year":"2012","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1080\/10428190902803677","article-title":"Enhanced formation and survival of CD4+ CD25hi Foxp3+ T-cells in chronic lymphocytic leukemia","volume":"50","author":"Jak","year":"2009","journal-title":"Leuk. Lymphoma"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.leukres.2017.07.004","article-title":"Quantitative and qualitative analysis of regulatory T cells in B cell chronic lymphocytic leukemia","volume":"60","author":"Mpakou","year":"2017","journal-title":"Leuk. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.1182\/blood-2010-12-324210","article-title":"A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease","volume":"117","author":"Bagnara","year":"2011","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/j.1600-065X.2009.00770.x","article-title":"CD28 and CTLA-4 coreceptor expression and signal transduction","volume":"229","author":"Rudd","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/bjh.12380","article-title":"Immune checkpoint blockade immunotherapy to activate anti-tumour T-cell immunity","volume":"162","author":"Ramsay","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1126\/science.1202947","article-title":"Trans-endocytosis of CD80 and CD86: A molecular basis for the cell-extrinsic function of CTLA-4","volume":"332","author":"Qureshi","year":"2011","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S1074-7613(01)00097-8","article-title":"CTLA-4 regulates induction of anergy in vivo","volume":"14","author":"Greenwald","year":"2001","journal-title":"Immunity"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1084\/jem.20082492","article-title":"Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies","volume":"206","author":"Peggs","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1038\/sj.bjc.6601833","article-title":"Alterations of the expression of T-cell-related costimulatory CD28 and downregulatory CD152 (CTLA-4) molecules in patients with B-cell chronic lymphocytic leukaemia","volume":"90","author":"Frydecka","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1038\/sj.leu.2403907","article-title":"Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia","volume":"19","author":"Motta","year":"2005","journal-title":"Leukemia"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4143","DOI":"10.1007\/s13277-015-4217-1","article-title":"Patients with chronic lymphocytic leukaemia (CLL) differ in the pattern of CTLA-4 expression on CLL cells: The possible implications for immunotherapy with CTLA-4 blocking antibody","volume":"37","author":"Ciszak","year":"2016","journal-title":"Tumour. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/sj.leu.2403588","article-title":"CTLA-4 overexpression in CD19+\/CD5+ cells correlates with the level of cell cycle regulators and disease progression in B-CLL patients","volume":"19","author":"Kosmaczewska","year":"2005","journal-title":"Leukemia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5295","DOI":"10.1158\/1078-0432.CCR-07-0283","article-title":"ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressing B-cell chronic lymphocytic leukemia","volume":"13","author":"Joshi","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Mittal, A.K., Chaturvedi, N.K., Rohlfsen, R.A., Gupta, P., Joshi, A.D., Hegde, G.V., Bociek, R.G., and Joshi, S.S. (2013). Role of CTLA4 in the proliferation and survival of chronic lymphocytic leukemia. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070352"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1182\/blood-2012-10-385591","article-title":"The role of B7 family molecules in hematologic malignancy","volume":"121","author":"Greaves","year":"2013","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2908","DOI":"10.3109\/10428194.2015.1017820","article-title":"The function of a novel immunophenotype candidate molecule PD-1 in chronic lymphocytic leukemia","volume":"56","author":"Grzywnowicz","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1084\/jem.20112741","article-title":"Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2","volume":"209","author":"Yokosuka","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1084\/jem.20090847","article-title":"PD-L1 regulates the development, maintenance, and function of induced regulatory T cells","volume":"206","author":"Francisco","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s00262-008-0591-5","article-title":"Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells","volume":"58","author":"Liu","year":"2009","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1158\/1078-0432.CCR-11-2630","article-title":"Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression","volume":"18","author":"Nunes","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Korona-Glowniak, I., Grywalska, E., Grzegorczyk, A., Rolinski, J., Glowniak, A., and Malm, A. (2019). Bacterial Colonization in Patients with Chronic Lymphocytic Leukemia and Factors Associated with Infections and Colonization. J. Clin. Med., 8.","DOI":"10.3390\/jcm8060861"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"953","DOI":"10.3324\/haematol.2012.077537","article-title":"The PD-1\/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia","volume":"98","author":"Brusa","year":"2013","journal-title":"Haematologica"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1182\/blood-2017-07-740993","article-title":"PD-1 expression and clinical PD-1 blockade in B-cell lymphomas","volume":"131","author":"Zhou","year":"2018","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1159\/000430980","article-title":"Expression of Programmed Death 1 Ligand in Different Compartments of Chronic Lymphocytic Leukemia","volume":"134","author":"Grzywnowicz","year":"2015","journal-title":"Acta Haematol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Haderk, F., Schulz, R., Iskar, M., Cid, L.L., Worst, T., Willmund, K.V., Schulz, A., Warnken, U., Seiler, J., and Benner, A. (2017). Tumor-derived exosomes modulate PD-L1 expression in monocytes. Sci. Immunol., 2.","DOI":"10.1126\/sciimmunol.aah5509"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"40558","DOI":"10.18632\/oncotarget.9941","article-title":"Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming","volume":"7","author":"Wu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5465","DOI":"10.1172\/JCI96610","article-title":"CD84 regulates PD-1\/PD-L1 expression and function in chronic lymphocytic leukemia","volume":"128","author":"Lewinsky","year":"2018","journal-title":"J. Clin. Invest."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1172\/JCI89756","article-title":"Ibrutinib treatment improves T cell number and function in CLL patients","volume":"127","author":"Long","year":"2017","journal-title":"J. Clin. Invest."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1038\/leu.2017.304","article-title":"Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1\/PD-L1 pathway","volume":"32","author":"Kondo","year":"2018","journal-title":"Leukemia"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1158\/1078-0432.CCR-15-1965","article-title":"Disruption of in vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib--Findings from an Investigator-Initiated Phase II Study","volume":"22","author":"Niemann","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1111\/bjh.15516","article-title":"Ibrutinib induces rapid down-regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia-related genes in blood and lymph nodes","volume":"183","author":"Palma","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3308","DOI":"10.1182\/blood-2013-05-504597","article-title":"Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing","volume":"122","author":"Dubovsky","year":"2013","journal-title":"Blood"},{"key":"ref_69","first-page":"E966","article-title":"Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK","volume":"112","author":"Kohrt","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1182\/blood-2012-02-411678","article-title":"Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: Establishing a reversible immune evasion mechanism in human cancer","volume":"120","author":"Ramsay","year":"2012","journal-title":"Blood"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1182\/blood-2015-02-626754","article-title":"Mechanisms of PD-L1\/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Emicro-TCL1 CLL mouse model","volume":"126","author":"McClanahan","year":"2015","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6955","DOI":"10.1073\/pnas.102181599","article-title":"Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression","volume":"99","author":"Bichi","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1158\/2326-6066.CIR-14-0040","article-title":"In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates","volume":"2","author":"Wang","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Jain, N., Basu, S., Thompson, P.A., Ohanian, M., Ferrajoli, A., Pemmaraju, N., Cortes, J.E., Estrov, Z., Burger, J.A., and Neelapu, S.S. (2016). Nivolumab Combined with Ibrutinib for CLL and Richter Transformation: A Phase II Trial. Blood, 128.","DOI":"10.1182\/blood.V128.22.59.59"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3393","DOI":"10.1182\/blood-2015-02-567453","article-title":"Immune checkpoint blockade in hematologic malignancies","volume":"125","author":"Armand","year":"2015","journal-title":"Blood"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/ni.1674","article-title":"The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells","volume":"10","author":"Yu","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"17647","DOI":"10.1074\/jbc.M114.572420","article-title":"T-cell immunoglobulin and ITIM domain (TIGIT) receptor\/poliovirus receptor (PVR) ligand engagement suppresses interferon-gamma production of natural killer cells via beta-arrestin 2-mediated negative signaling","volume":"289","author":"Li","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/cdd.2012.141","article-title":"Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells","volume":"20","author":"Liu","year":"2013","journal-title":"Cell Death Differ."},{"key":"ref_79","first-page":"418","article-title":"Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators","volume":"6","author":"Lines","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.4049\/jimmunol.175.3.1558","article-title":"CD226 is specifically expressed on the surface of Th1 cells and regulates their expansion and effector functions","volume":"175","author":"Dardalhon","year":"2005","journal-title":"J. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"17858","DOI":"10.1073\/pnas.0903474106","article-title":"The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity","volume":"106","author":"Stanietsky","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1158\/1078-0432.CCR-15-2626","article-title":"T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients","volume":"22","author":"Kong","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1038\/sj.onc.1208409","article-title":"Transcriptional activation of the mouse Necl-5\/Tage4\/PVR\/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway","volume":"24","author":"Hirota","year":"2005","journal-title":"Oncogene"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1182\/blood-2008-08-173914","article-title":"ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype","volume":"113","author":"Soriani","year":"2009","journal-title":"Blood"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Kamran, N., Takai, Y., Miyoshi, J., Biswas, S.K., Wong, J.S., and Gasser, S. (2013). Toll-like receptor ligands induce expression of the costimulatory molecule CD155 on antigen-presenting cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054406"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"902","DOI":"10.4049\/jimmunol.0903225","article-title":"DNAM-1\/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases","volume":"184","author":"Chan","year":"2010","journal-title":"J. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1093\/intimm\/dxl031","article-title":"LFA-1-dependent lipid raft recruitment of DNAM-1 (CD226) in CD4+ T cell","volume":"18","author":"Shirakawa","year":"2006","journal-title":"Int. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1084\/jem.20030958","article-title":"CD226 (DNAM-1) is involved in lymphocyte function-associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation","volume":"198","author":"Shibuya","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.ccell.2014.10.018","article-title":"The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function","volume":"26","author":"Johnston","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_90","first-page":"1918","article-title":"Increased expression of TIGIT on CD4+ T cells ameliorates immune-mediated bone marrow failure of aplastic anemia","volume":"115","author":"Zhang","year":"2014","journal-title":"J. Cell Biochem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1002\/eji.200940234","article-title":"Loss of DNAM-1 contributes to CD8+ T-cell exhaustion in chronic HIV-1 infection","volume":"40","author":"Cella","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"145","DOI":"10.4049\/jimmunol.1402381","article-title":"Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226","volume":"195","author":"Fuhrman","year":"2015","journal-title":"J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1172\/JCI80445","article-title":"TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients","volume":"125","author":"Chauvin","year":"2015","journal-title":"J. Clin. Invest."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/JID.2015.404","article-title":"Melanoma Cells Control Antimelanoma CTL Responses via Interaction between TIGIT and CD155 in the Effector Phase","volume":"136","author":"Inozume","year":"2016","journal-title":"J. Invest. Dermatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e1371399","DOI":"10.1080\/2162402X.2017.1371399","article-title":"TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia","volume":"7","author":"Catakovic","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"11520","DOI":"10.1073\/pnas.94.21.11520","article-title":"Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis","volume":"94","author":"Goncalves","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S1044-579X(03)00023-3","article-title":"HLA-G in cancer: A way to turn off the immune system","volume":"13","author":"Moreau","year":"2003","journal-title":"Semin. Cancer Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"10139","DOI":"10.1158\/0008-5472.CAN-05-0097","article-title":"HLA-G proteins in cancer: Do they provide tumor cells with an escape mechanism?","volume":"65","author":"Moreau","year":"2005","journal-title":"Cancer Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/j.humimm.2003.08.345","article-title":"Soluble HLA-G molecules are increased in lymphoproliferative disorders","volume":"64","author":"Sebti","year":"2003","journal-title":"Hum. Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1016\/j.leukres.2008.04.008","article-title":"The significance of soluble HLA-G plasma levels as well as messenger HLA-G for B-cell chronic lymphocytic leukemia (B-CLL)","volume":"32","author":"Giannopoulos","year":"2008","journal-title":"Leuk. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1182\/blood-2004-08-3335","article-title":"HLA-G expression is associated with an unfavorable outcome and immunodeficiency in chronic lymphocytic leukemia","volume":"105","author":"Nuckel","year":"2005","journal-title":"Blood"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1179\/102453309X385197","article-title":"HLA-G expression in B chronic lymphocytic leukemia: A new prognostic marker?","volume":"14","author":"Erikci","year":"2009","journal-title":"Hematology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/j.1751-553X.2008.01030.x","article-title":"Prognostic irrelevance of HLA-G in B-cell chronic lymphocytic leukemia","volume":"31","author":"Rosado","year":"2009","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s00251-004-0673-2","article-title":"HLA-G and IL-10 in serum in relation to HLA-G genotype and polymorphisms","volume":"56","author":"Hviid","year":"2004","journal-title":"Immunogenetics"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"888","DOI":"10.3324\/haematol.2013.095281","article-title":"HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: Impact of the HLA-G 14 base pair (rs66554220) polymorphism","volume":"99","author":"Rizzo","year":"2014","journal-title":"Haematologica"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1053\/j.seminhematol.2014.05.007","article-title":"The B-cell receptor pathway: A critical component of healthy and malignant immune biology","volume":"51","author":"Zhong","year":"2014","journal-title":"Semin. Hematol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/leu.2016.322","article-title":"Antigen receptor stereotypy in chronic lymphocytic leukemia","volume":"31","author":"Stamatopoulos","year":"2017","journal-title":"Leukemia"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.autrev.2007.02.014","article-title":"From normal to clonal B cells: Chronic lymphocytic leukemia (CLL) at the crossroad between neoplasia and autoimmunity","volume":"7","author":"Ghia","year":"2007","journal-title":"Autoimmun. Rev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nature11309","article-title":"Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling","volume":"489","author":"Ubelhart","year":"2012","journal-title":"Nature"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1182\/blood-2010-05-284984","article-title":"The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia","volume":"117","author":"Herishanu","year":"2011","journal-title":"Blood"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41389-017-0011-9","article-title":"The hypoxic tumour microenvironment","volume":"7","author":"Petrova","year":"2018","journal-title":"Oncogenesis"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1172\/JCI67230","article-title":"HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations","volume":"123","author":"Semenza","year":"2013","journal-title":"J. Clin. Invest."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2015.12.006","article-title":"The Emerging Hallmarks of Cancer Metabolism","volume":"23","author":"Pavlova","year":"2016","journal-title":"Cell Metab."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1182\/blood-2005-05-1795","article-title":"Tumor-derived lactic acid modulates dendritic cell activation and antigen expression","volume":"107","author":"Gottfried","year":"2006","journal-title":"Blood"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1182\/blood-2006-07-035972","article-title":"Inhibitory effect of tumor cell-derived lactic acid on human T cells","volume":"109","author":"Fischer","year":"2007","journal-title":"Blood"},{"key":"ref_116","first-page":"453","article-title":"Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release","volume":"39","author":"Goetze","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nature13490","article-title":"Functional polarization of tumour-associated macrophages by tumour-derived lactic acid","volume":"513","author":"Colegio","year":"2014","journal-title":"Nature"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1182\/bloodadvances.2016000984","article-title":"Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment","volume":"1","author":"Serra","year":"2016","journal-title":"Blood Adv."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/leu.2015.187","article-title":"Metabolic plasticity in CLL: Adaptation to the hypoxic niche","volume":"30","author":"Koczula","year":"2016","journal-title":"Leukemia"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/ni.3269","article-title":"Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants","volume":"16","author":"Galgani","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/imr.12571","article-title":"Extracellular nucleosides and nucleotides as immunomodulators","volume":"280","author":"Kepp","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.3389\/fimmu.2019.02301","article-title":"Ectonucleotidases in Blood Malignancies: A Tale of Surface Markers and Therapeutic Targets","volume":"10","author":"Vaisitti","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nrc3340","article-title":"The NAD metabolome--a key determinant of cancer cell biology","volume":"12","author":"Chiarugi","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.3389\/fimmu.2019.01720","article-title":"NAD-Biosynthetic and Consuming Enzymes as Central Players of Metabolic Regulation of Innate and Adaptive Immune Responses in Cancer","volume":"10","author":"Audrito","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_125","first-page":"1431","article-title":"Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor","volume":"14","author":"Samal","year":"1994","journal-title":"Mol. Cell Biol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1182\/blood-2014-07-589069","article-title":"Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia","volume":"125","author":"Audrito","year":"2015","journal-title":"Blood"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"13135","DOI":"10.1038\/srep13135","article-title":"Unique Toll-Like Receptor 4 Activation by NAMPT\/PBEF Induces NFkappaB Signaling and Inflammatory Lung Injury","volume":"5","author":"Camp","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/nrc3613","article-title":"Immunity, inflammation and cancer: A leading role for adenosine","volume":"13","author":"Antonioli","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00109-012-0991-z","article-title":"Biological functions of ecto-enzymes in regulating extracellular adenosine levels in neoplastic and inflammatory disease states","volume":"91","author":"Longhi","year":"2013","journal-title":"J. Mol. Med."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.bbamem.2010.09.020","article-title":"Adenosine receptors and cancer","volume":"1808","author":"Gessi","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/414916a","article-title":"Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage","volume":"414","author":"Ohta","year":"2001","journal-title":"Nature"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nrc.2017.86","article-title":"Targeting immunosuppressive adenosine in cancer","volume":"17","author":"Vijayan","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"6141","DOI":"10.1182\/blood-2011-08-374728","article-title":"CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death","volume":"118","author":"Serra","year":"2011","journal-title":"Blood"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"5947","DOI":"10.1158\/1078-0432.CCR-08-0229","article-title":"Hypoxia-adenosinergic immunosuppression: Tumor protection by T regulatory cells and cancerous tissue hypoxia","volume":"14","author":"Sitkovsky","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1182\/blood-2015-06-651380","article-title":"Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed\/refractory diffuse large B-cell lymphoma","volume":"127","author":"Viardot","year":"2016","journal-title":"Blood"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.jcyt.2019.04.005","article-title":"The efficacy of anti-CD19 chimeric antigen receptor T cells for B-cell malignancies","volume":"21","author":"Cao","year":"2019","journal-title":"Cytotherapy"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.1182\/blood-2017-02-765685","article-title":"Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL","volume":"129","author":"Ding","year":"2017","journal-title":"Blood"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1016\/S2352-3026(18)30217-5","article-title":"Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: A phase 1\/2a study","volume":"6","author":"Younes","year":"2019","journal-title":"Lancet Haematol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/leu.2014.146","article-title":"Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL","volume":"29","author":"Middleton","year":"2015","journal-title":"Leukemia"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1080\/14712598.2018.1508444","article-title":"The latest developments with anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia","volume":"18","author":"Evers","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1126\/science.aar6711","article-title":"CAR T cell immunotherapy for human cancer","volume":"359","author":"June","year":"2018","journal-title":"Science"},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Porter, D.L., Hwang, W.T., Frey, N.V., Lacey, S.F., Shaw, P.A., Loren, A.W., Bagg, A., Marcucci, K.T., Shen, A., and Gonzalez, V. (2015). Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med., 7.","DOI":"10.1126\/scitranslmed.aac5415"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1002\/ajh.25457","article-title":"Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: The development and challenges of chimeric antigen receptor T-cell therapy for chronic lymphocytic leukemia","volume":"94","author":"Bair","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Hofland, T., Eldering, E., Kater, A.P., and Tonino, S.H. (2019). Engaging Cytotoxic T and NK Cells for Immunotherapy in Chronic Lymphocytic Leukemia. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20174315"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1825\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:04:48Z","timestamp":1760173488000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1825"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,6]]},"references-count":144,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["ijms21051825"],"URL":"https:\/\/doi.org\/10.3390\/ijms21051825","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,6]]}}}