CXCL10 Recruitment of γδ T Cells into the Hypoxic Bone Marrow Environment Leads to IL17 Expression and Multiple Myeloma Progression

被引:4
|
作者
Wang, Jingya [1 ]
Peng, Ziyi [1 ]
Guo, Jing [1 ]
Wang, Yixuan [1 ]
Wang, Sheng [1 ]
Jiang, Hongmei [1 ]
Wang, Mengqi [1 ]
Xie, Ying [1 ]
Li, Xin [1 ]
Hu, Meilin [2 ]
Xie, Yangyang [1 ]
Cheng, Hao [1 ]
Li, Tiantian [1 ]
Jia, Linchuang [1 ]
Song, Jia [3 ]
Wang, Yafei [4 ,6 ]
Hou, Jian [5 ,7 ]
Liu, Zhiqiang [1 ,8 ]
机构
[1] Tianjin Med Univ, Prov & Minist Cosponsored Collaborat Innovat Ctr M, Sch Basic Med Sci, Dept Physiol & Pathophysiol,State Key Lab Expt Hem, Tianjin, Peoples R China
[2] Tianjin Med Univ, Sch Stomatol, Tianjin, Peoples R China
[3] Tianjin Med Univ, Gen Hosp, Dept Hematol, Tianjin, Peoples R China
[4] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Tianjins Clin Res Ctr Canc, Dept Hematol,Key Lab Canc Prevent & Therapy, Tianjin, Peoples R China
[5] Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med, Dept Hematol, Shanghai, Peoples R China
[6] Tianjin Med Univ Canc Inst, Hosp, Dept Hematol, Tianjin 300060, Peoples R China
[7] Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med, Dept Hematol, Shanghai 200127, Peoples R China
[8] Tianjin Med Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Tianjin 300070, Peoples R China
关键词
HELPER; 17; CELLS; PERIPHERAL-BLOOD; IL-17; DIFFERENTIATION; MICROENVIRONMENT; LYMPHOCYTES; ACTIVATION; PHENOTYPE; EXPANSION; MODEL;
D O I
10.1158/2326-6066.CIR-23-0088
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The authors show BMSCs induce MM-cell secretion of CXCL10, recruiting gamma delta T cells to BM. Hypoxia in the BM activates a SRC-3/ROR gamma t/IL17 axis in the gamma delta T cells that can be targeted to reduce immunosuppression and MM progression. In multiple myeloma (MM), bone marrow stromal cells (BMSC) shape a unique niche within the bone marrow, promoting T-cell dysfunction and driving MM progression; however, the precise underlying mechanisms remain elusive. Here, we show that BMSC-mediated reprogramming of MM cells led to heightened production of CXCL10. CXCL10 orchestrated the recruitment of gamma delta T cells into the bone marrow, and this was observed in both the Vk*MYC and 5TGM1 mouse models of MM, as well as in patients experiencing refractory or relapsed MM. Furthermore, the dysfunctional gamma delta T cells in the MM bone marrow niche exhibited increased PD-1 expression and IL17 production. In the Vk*MYC mouse model, MM-associated bone lesions and mortality were markedly alleviated in Tcrd-/- mice, and MM disease progression could be rescued in these mice upon transplantation of gamma delta T cells expanded from wild-type mice, but not from Il17-/- mice. Mechanistically, the hypoxic microenvironment prevailing in the MM bone marrow niche stimulated the expression of steroid receptor coactivator 3 (SRC-3) in gamma delta T cells, which in turn interacted with the transcriptional factor ROR gamma t, promoting Il17 transcription. Pharmacologic inhibition of SRC-3 utilizing SI-2 effectively suppressed Il17A expression in gamma delta T cells, leading to alleviation of MM progression in the murine models and enhancing the anti-multiple myeloma efficacy of bortezomib. Our results illuminated the bone marrow microenvironment's involvement in provoking gamma delta T-cell dysfunction throughout MM progression and suggest SRC-3 inhibition as a promising strategy to enhance the effectiveness of immunotherapies targeting gamma delta T cells.
引用
收藏
页码:1384 / 1399
页数:16
相关论文
共 32 条
  • [21] Influence of lovastatin on BCL-2 and BAX expression by plasma cells and T lymphocytes in short-term cultures of multiple myeloma bone marrow mononuclear cells
    Dmoszynska, A
    Podhorecka, M
    Rolinski, J
    Soroka-Wojatszko, M
    POLISH JOURNAL OF PHARMACOLOGY, 2004, 56 (04): : 485 - 489
  • [22] Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor
    Mekhloufi, Abdelilah
    Kosta, Andrea
    Stabile, Helena
    Molfetta, Rosa
    Zingoni, Alessandra
    Soriani, Alessandra
    Cippitelli, Marco
    Paolini, Rossella
    Gismondi, Angela
    Ricciardi, Maria Rosaria
    Petrucci, Maria Teresa
    Masuelli, Laura
    Caracciolo, Giulio
    Palchetti, Sara
    Santoni, Angela
    Fionda, Cinzia
    CANCERS, 2020, 12 (02)
  • [23] Increased Expression Of PD-1 Checkpoint Molecule on Bone Marrow T-Cells from Patients With Multiple Myeloma: Potential Impact on Clinical Outcome?
    Perez-Montero, Pablo
    Paniagua, Angel
    Prieto, Mario
    Llorente, Laura
    Serrano, Alfons
    Mari, Pilar
    Rodrigo, Esther
    Varea, Sara
    Lopez Rios, Fernando
    Perez de Oteyza, Jaime
    CLINICAL LYMPHOMA MYELOMA & LEUKEMIA, 2019, 19 (10): : E109 - E109
  • [24] Bone marrow mesenchymal stem cells suppress activated CD4+ T cells proliferation through TGF-beta and IL10 dependent of autophagy in pathological hypoxic microenvironment
    Zhang, Yan
    Liu, Liang
    Wang, Xiaobo
    Shen, Xuezhen
    Pei, Yilun
    Liu, Yi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2024, 702
  • [25] DYSFUNCTIONAL BONE MARROW AND CIRCULATING.d T CELLS PREDICT A HIGH RISK OF PROGRESSION FROM PRE-MALIGNANT PLASMA CELL DYSCRASIAS TO SYMPTOMATIC MULTIPLE MYELOMA
    Corsale, A. M.
    Azgomi, M. Shekarkar
    Plano, F.
    Di Simone, M.
    Perez, C.
    Gigliotta, E.
    Speciale, M.
    Aquilina, C.
    Vullo, C.
    Garofano, F.
    Camarda, G.
    Rotolo, C.
    Santoro, M.
    Caccamo, N.
    Paiva, B.
    Siragusa, S.
    Dieli, F.
    Meraviglia, S.
    Botta, C.
    HAEMATOLOGICA, 2024, 109 : 29 - 30
  • [26] BONE MARROW-DERIVED SUPPRESSOR CELLS AMELIORATE LIVER FIBROSIS VIA ENHANCED IL-10 EXPRESSION AND EXPANSION OF INTRAHEPATIC REGULATORY T CELLS IN MOUSE LIVER
    Suh, Yang-Gun
    Byun, Jin-Seok
    Yi, Hyon-Seung
    Lee, Young-Sun
    Jeong, Won-Il
    HEPATOLOGY, 2011, 54 : 745A - 745A
  • [27] Detection and follow-up of fibroblast growth factor receptor 3 expression on bone marrow and circulating plasma cells by flow cytometry in patients with t(4;14) multiple myeloma
    Chandesris, M. O.
    Soulier, J.
    Labaume, S.
    Crinquette, A.
    Repellini, L.
    Chemin, K.
    Malphettes, M.
    Fieschi, C.
    Asli, B.
    Uzunhan, Y.
    Fermand, J. P.
    Bories, J. C.
    Arnulf, B.
    BRITISH JOURNAL OF HAEMATOLOGY, 2007, 136 (04) : 609 - 614
  • [28] The expression of PD-1 alone by T cells is associated with cell activation while the co-expression of TIM-3 indicates exhausted subsets both in peripheral blood and bone marrow of multiple myeloma patients
    Batorov, E.
    Sergeevicheva, V.
    Aristova, T.
    Sizikova, S.
    Ushakova, G.
    Maximova, A.
    Morenkova, A.
    Shevela, E.
    Ostanin, A.
    Chernykh, E.
    ANNALS OF ONCOLOGY, 2019, 30
  • [29] Bone marrow stromal cells derived exosomal miR-10a and miR-16 may be involved in progression of patients with multiple myeloma by regulating EPHA8 or IGF1R/CCND1
    Peng, Ye
    Song, Xiaolu
    Lan, Jianping
    Wang, Xiaogang
    Wang, Manling
    MEDICINE, 2021, 100 (04)
  • [30] High PD-1 and Tim-3 Expression Concurrent with Exhausted CD4+and CD8+T Cells in Bone Marrow Compared with Peripheral Blood from Patients with Multiple Myeloma
    Tan, Jiaxiong
    Chen, Shaohua
    Huang, Jingying
    Chen, Youchun
    Yang, Lijian
    Zhong, Jun
    Lu, Yuhong
    Li, Yangqiu
    BLOOD, 2017, 130