{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:48:34Z","timestamp":1789213714898,"version":"build-2803163510"},"reference-count":43,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81670184"],"award-info":[{"award-number":["81670184"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770213"],"award-info":[{"award-number":["81770213"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Key New Drug Creation Special Programs","award":["2017ZX09304-021"],"award-info":[{"award-number":["2017ZX09304-021"]}]},{"name":"National Key New Drug Creation Special Programs","award":["2018ZX09201015"],"award-info":[{"award-number":["2018ZX09201015"]}]},{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin","doi-asserted-by":"crossref","award":["18JCZDJC45100"],"award-info":[{"award-number":["18JCZDJC45100"]}],"id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin","doi-asserted-by":"crossref","award":["19JCYBJC26500"],"award-info":[{"award-number":["19JCYBJC26500"]}],"id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Human Genetic Resources Sharing Service Platform","award":["2005DKA21300"],"award-info":[{"award-number":["2005DKA21300"]}]},{"name":"Cancer biobank of Tianjin Medical University Cancer Institute and Hospital"},{"name":"Projects of the Tianjin Municipal Health Bureau","award":["15KG145"],"award-info":[{"award-number":["15KG145"]}]},{"name":"Clinical Oncology Research Fund of CSCO","award":["Y-XD2019-162"],"award-info":[{"award-number":["Y-XD2019-162"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,3,14]]},"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Targeting the PD-1\/PD-L1\/L2 (programmed cell death protein 1\/programmed cell death ligand 1\/ligand 2) pathway combined with other immunosuppressive signalings, such as CD73\/A2aR (A2a adenosine receptor) adenosine signaling, has emerged as a promising strategy for cancer treatment. The genetic characteristics of these immune checkpoints need to be further investigated in diffuse large B-cell lymphoma (DLBCL).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed whole-exome sequencing\/targeted deep sequencing to investigate the genetic characteristics of PD-1\/PD-L1\/L2 and CD73\/A2aR. The immunosuppressive effect of these two pathways on the tumor microenvironment was evaluated via RNA sequencing. Single-cell RNA sequencing was further applied to investigate the dysfunctional CD8+ T cells. In addition, multiplex immunofluorescence staining was used to quantitatively assess the expression of dysfunctional CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in DLBCL.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SP140 was identified as a novel translocation partner for PD-L1, and a new inversion was detected between PD-L1 and PD-L2, both leading to the upregulation of PD-L1 expression. CD73 genetic mutations did not increase mRNA and protein expression. Patients with genetically altered CD73 tended to have a better overall survival than patients with wild-type CD73. Both PD-1\/PD-L1 and CD73\/A2aR signaling mediated the immunosuppressive microenvironment in DLBCL. The numbers of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells with PD-1 and A2aR expression were positively correlated with the number of dysfunctional CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells (R\n                      <jats:sup>2<\/jats:sup>\n                      =0.974, p\n                      <jats:italic>=<\/jats:italic>\n                      0.013). According to the grades of dysfunctional CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells we defined,\n                      <jats:italic>grade<\/jats:italic>\n                      1 dysfunctional CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, with either PD-1\n                      <jats:sup>+<\/jats:sup>\n                      or A2aR\n                      <jats:sup>+<\/jats:sup>\n                      , were significantly associated with poorer survival than\n                      <jats:italic>grade<\/jats:italic>\n                      0 dysfunctional CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, with both PD-1\n                      <jats:sup>\u2212<\/jats:sup>\n                      and A2aR\n                      <jats:sup>\u2212<\/jats:sup>\n                      ; and patients with\n                      <jats:italic>grade<\/jats:italic>\n                      2 dysfunctional CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells showed the worst clinical outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study describes the additional genetic basis of PD-L1 overexpression and characterizes certain genetic alterations of CD73\/A2aR in DLBCL. The degree of T-cell dysfunction is correlated with clinical outcomes. Strategies that reverse T-cell dysfunction by inhibiting PD-1\/PD-L1\/L2, particularly in combination with CD73\/A2aR, may show potential as effective therapeutic options for DLBCL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2021-004114","type":"journal-article","created":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T12:14:59Z","timestamp":1648815299000},"page":"e004114","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":69,"title":["Genetic characteristics involving the PD-1\/PD-L1\/L2 and CD73\/A2aR axes and the immunosuppressive microenvironment in DLBCL"],"prefix":"10.1136","volume":"10","clinical-trial-number":[{"clinical-trial-number":"nct02403193","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02655822","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Tingting","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin\u2019s Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin\u2019s Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Jiao","sequence":"additional","affiliation":[{"name":"Panovue Biological Technology Co., Ltd, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Marvel Medical Laboratory, Tianjin Marvelbio Technology Co., Ltd, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"He","sequence":"additional","affiliation":[{"name":"Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin\u2019s Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanfang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin\u2019s Clinical 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin\u2019s Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchen","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 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