Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL
Background 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 gen...
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BMJ Publishing Group
2022-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/4/e004114.full |
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| author | Tingting Zhang Zhenzhen Zhang Xiubao Ren Jin He Zhengzi Qian Bin Meng Lei Jiao Hengqi Liu Lanfang Li Lihua Qiu Shiyong Zhou Wenchen Gong Huilai Zhang Xianhuo Wang |
| author_facet | Tingting Zhang Zhenzhen Zhang Xiubao Ren Jin He Zhengzi Qian Bin Meng Lei Jiao Hengqi Liu Lanfang Li Lihua Qiu Shiyong Zhou Wenchen Gong Huilai Zhang Xianhuo Wang |
| author_sort | Tingting Zhang |
| collection | DOAJ |
| description | Background 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).Methods 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+ T cells in DLBCL.Results 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+ T cells with PD-1 and A2aR expression were positively correlated with the number of dysfunctional CD8+ T cells (R2=0.974, p=0.013). According to the grades of dysfunctional CD8+ T cells we defined, grade 1 dysfunctional CD8+ T cells, with either PD-1+ or A2aR+, were significantly associated with poorer survival than grade 0 dysfunctional CD8+ T cells, with both PD-1− and A2aR−; and patients with grade 2 dysfunctional CD8+ T cells showed the worst clinical outcomes.Conclusions 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. |
| format | Article |
| id | doaj-art-2301539d33c94ce1acbcbd27b09c91e6 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-2301539d33c94ce1acbcbd27b09c91e62025-02-03T20:35:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-04-0110410.1136/jitc-2021-004114Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCLTingting Zhang0Zhenzhen Zhang1Xiubao Ren2Jin He3Zhengzi Qian4Bin Meng5Lei Jiao6Hengqi Liu7Lanfang Li8Lihua Qiu9Shiyong Zhou10Wenchen Gong11Huilai Zhang12Xianhuo Wang131 Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing, China3 Marvel Medical Laboratory, Tianjin Marvelbio Technology Co., Ltd, Tianjin, ChinaDepartment of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaDepartment of Endocrinology and Nephrology, Chonggang General Hospital, Chongqing, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute & Hospital, Tianjin, ChinaAssisted reproduction center, Northwest Women and Children`s Hospital, Xi`an, China2 Panovue Biological Technology Co., Ltd, Beijing, China1 Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China1 Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China1 Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China1 Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China4 Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China1 Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaBackground 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).Methods 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+ T cells in DLBCL.Results 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+ T cells with PD-1 and A2aR expression were positively correlated with the number of dysfunctional CD8+ T cells (R2=0.974, p=0.013). According to the grades of dysfunctional CD8+ T cells we defined, grade 1 dysfunctional CD8+ T cells, with either PD-1+ or A2aR+, were significantly associated with poorer survival than grade 0 dysfunctional CD8+ T cells, with both PD-1− and A2aR−; and patients with grade 2 dysfunctional CD8+ T cells showed the worst clinical outcomes.Conclusions 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.https://jitc.bmj.com/content/10/4/e004114.full |
| spellingShingle | Tingting Zhang Zhenzhen Zhang Xiubao Ren Jin He Zhengzi Qian Bin Meng Lei Jiao Hengqi Liu Lanfang Li Lihua Qiu Shiyong Zhou Wenchen Gong Huilai Zhang Xianhuo Wang Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL Journal for ImmunoTherapy of Cancer |
| title | Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL |
| title_full | Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL |
| title_fullStr | Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL |
| title_full_unstemmed | Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL |
| title_short | Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL |
| title_sort | genetic characteristics involving the pd 1 pd l1 l2 and cd73 a2ar axes and the immunosuppressive microenvironment in dlbcl |
| url | https://jitc.bmj.com/content/10/4/e004114.full |
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