Anergic bone marrow Vγ9Vδ2 T cells as early and long-lasting markers of PD-1-targetable microenvironment-induced immune suppression in human myeloma

被引:61
作者
Castella, Barbara [1 ,2 ]
Foglietta, Myriam [1 ,2 ]
Sciancalepore, Patrizia [1 ,3 ]
Rigoni, Micol [1 ,2 ]
Coscia, Marta [1 ,2 ,3 ]
Griggio, Valentina [1 ,2 ]
Vitale, Candida [1 ,3 ]
Ferracini, Riccardo [4 ]
Saraci, Elona [3 ]
Omede, Paola [3 ]
Riganti, Chiara [5 ]
Palumbo, Antonio [3 ]
Boccadoro, Mario [3 ]
Massaia, Massimo [1 ,2 ]
机构
[1] Ctr Ric Med Sperimentale CeRMS, Lab Ematol Oncol, Turin, Italy
[2] Univ Turin, Dipartimento Biotecnol Mol & Sci Salute, Turin, Italy
[3] Univ Turin, SC Ematol 1, Turin, Italy
[4] Azienda Osped Univ Citta Salute & Sci Torino, Div Ortopedia, Turin, Italy
[5] Univ Turin, Dipartimento Oncol, Turin, Italy
来源
ONCOIMMUNOLOGY | 2015年 / 4卷 / 11期
关键词
MDSC; multiple myeloma; PD-1/PDL-1; pathway; V gamma 9V delta 2 T cells; MULTIPLE-MYELOMA; ZOLEDRONIC ACID; ANTI-PD-1; ANTIBODY; DENDRITIC CELLS; TUMOR-CELLS; GAMMA; EXPRESSION; BLOCKADE; PD-L1; ACTIVATION;
D O I
10.1080/2162402X.2015.1047580
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
V gamma 9V delta 2 T cells have a natural inclination to recognize malignant B cells in vitro via receptors for stress-induced self-ligands and TCR-dependent recognition of phosphoantigens (pAgs) generated in the mevalonate (Mev) pathway. This inclination is continuously challenged in vivo by the immune suppression operated by tumor cells. Multiple myeloma ( MM) is a prototypic B-cell malignancy in which myeloma cells subvert the local microenvironment to reshape antitumor immune responses. In this study, we have investigated the immune competence of bone marrow ( BM) V gamma 9V delta 2 T cells in a large series of MM patients. We have found that the BM microenvironment significantly hampers the pAg-reactivity of BM V gamma 9V delta 2 T cells, which become largely PD-1(+) and are surrounded by PD-L1(+) myeloma cells and increased numbers of PD-L1(+) myeloid-derived suppressor cells (MDSC). V gamma 9V delta 2 T-cell dysfunction is an early event that can be already detected in individuals with monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even when MM patients achieve clinical remission. Anti-PD-1 treatment increases the cytotoxic potential of V gamma 9V delta 2 T cells by almost 5-fold after pAg stimulation, and appears to be a promising strategy for effective immune interventions in MM.
引用
收藏
页数:11
相关论文
共 36 条
  • [1] Clinical and immunological evaluation of zoledronate-activated Vγ9γδ T-cell-based immunotherapy for patients with multiple myeloma
    Abe, Yu
    Muto, Masato
    Nieda, Mie
    Nakagawa, Yasunori
    Nicol, Andrew
    Kaneko, Touru
    Goto, Shigenori
    Yokokawa, Kiyoshi
    Suzuki, Kenshi
    [J]. EXPERIMENTAL HEMATOLOGY, 2009, 37 (08) : 956 - 968
  • [2] Relationship between CD107a expression and cytotoxic activity
    Aktas, Esin
    Kucuksezer, Umut Can
    Bilgic, Sema
    Erten, Gaye
    Deniz, Gunnur
    [J]. CELLULAR IMMUNOLOGY, 2009, 254 (02) : 149 - 154
  • [3] [Anonymous], 2011, STRATEGICAL DEV IND, DOI DOI 10.1016/J.SUSC0M.2010.10.002
  • [4] The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody
    Benson, Don M., Jr.
    Bakan, Courtney E.
    Mishra, Anjali
    Hofmeister, Craig C.
    Efebera, Yvonne
    Becknell, Brian
    Baiocchi, Robert A.
    Zhang, Jianying
    Yu, Jianhua
    Smith, Megan K.
    Greenfield, Carli N.
    Porcu, Pierluigi
    Devine, Steven M.
    Rotem-Yehudar, Rinat
    Lozanski, Gerard
    Byrd, John C.
    Caligiuri, Michael A.
    [J]. BLOOD, 2010, 116 (13) : 2286 - 2294
  • [5] Immune Modulation by Zoledronic Acid in Human Myeloma: An Advantageous Cross-Talk between Vγ9Vδ2 T Cells, αβ CD8+ T Cells, Regulatory T Cells, and Dendritic Cells
    Castella, Barbara
    Riganti, Chiara
    Fiore, Francesca
    Pantaleoni, Francesca
    Canepari, Maria Elisa
    Peola, Silvia
    Foglietta, Myriam
    Palumbo, Antonio
    Bosia, Amalia
    Coscia, Marta
    Boccadoro, Mario
    Massaia, Massimo
    [J]. JOURNAL OF IMMUNOLOGY, 2011, 187 (04) : 1578 - 1590
  • [6] Vγ9Vδ2 T cell-based immunotherapy in hematological malignancies: from bench to bedside
    Castella, Barbara
    Vitale, Candida
    Coscia, Marta
    Massaia, Massimo
    [J]. CELLULAR AND MOLECULAR LIFE SCIENCES, 2011, 68 (14) : 2419 - 2432
  • [7] Differentiation of effector/memory Vδ2 T cells and migratory routes in lymph nodes or inflammatory sites
    Dieli, F
    Poccia, F
    Lipp, M
    Sireci, G
    Caccamo, N
    Di Sano, C
    Salerno, A
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 198 (03) : 391 - 397
  • [8] Chemical synthesis and biological activity of bromohydrin pyrophosphate, a potent stimulator of human γδ T cells
    Espinosa, E
    Belmant, C
    Pont, F
    Luciani, B
    Poupot, R
    Romagné, F
    Brailly, H
    Bonneville, M
    Fournié, JJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (21) : 18337 - 18344
  • [9] Myeloid derived suppressor cells are numerically, functionally and phenotypically different in patients with multiple myeloma
    Favaloro, James
    Liyadipitiya, Tulita
    Brown, Ross
    Yang, Shihong
    Suen, Hayley
    Woodland, Narelle
    Nassif, Najah
    Hart, Derek
    Fromm, Phillip
    Weatherburn, Claire
    Gibson, John
    Ho, P. Joy
    Joshua, Douglas
    [J]. LEUKEMIA & LYMPHOMA, 2014, 55 (12) : 2893 - 2900
  • [10] Enhanced ability of dendritic cells to stimulate innate and adaptive immunity on short-term incubation with zoledronic acid
    Fiore, Francesca
    Castella, Barbara
    Nuschak, Barbara
    Bertieri, Raffaello
    Mariani, Sara
    Bruno, Benedetto
    Pantaleoni, Francesca
    Foglietta, Myriam
    Boccadoro, Mario
    Massaia, Massimo
    [J]. BLOOD, 2007, 110 (03) : 921 - 927