Disruption of CD8+ Treg Activity Results in Expansion of T Follicular Helper Cells and Enhanced Antitumor Immunity

被引:46
作者
Arias, Diana A. Alvarez [1 ,3 ]
Kim, Hye-Jung [1 ,3 ]
Zhou, Penghui [1 ,3 ]
Holderried, Tobias A. W. [1 ,3 ,5 ]
Wang, Xuan [1 ]
Dranoff, Glenn [1 ,2 ,4 ]
Cantor, Harvey [1 ,3 ]
机构
[1] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA
[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[3] Harvard Univ, Dept Microbiol & Immunol, Div Immunol, Sch Med, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
[5] Univ Dusseldorf, Dept Gastroenterol Hepatol & Infect Dis, Dusseldorf, Germany
关键词
MONOCLONAL-ANTIBODY; DENDRITIC CELLS; SYSTEMIC-LUPUS; TUMOR-CELLS; IMMUNOTHERAPY; RESPONSES; POTENT; DNA; AUTOANTIBODIES; INFLAMMATION;
D O I
10.1158/2326-6066.CIR-13-0121
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Tumor growth is associated with the inhibition of host antitumor immune responses that can impose serious obstacles to cancer immunotherapy. To define the potential contribution of Qa-1-restricted CD8 regulatory T cells (Treg) to the development of tumor immunity, we studied B6.Qa-1 D227K mice that harbor a point mutation in the MHC class Ib molecule Qa-1 that impairs CD8 Treg suppressive activity. Here, we report that the growth of B16 melanoma is substantially delayed in these Qa-1-mutant mice after therapeutic immunization with B16 melanoma cells engineered to express granulocyte macrophage colony-stimulating factor compared with Qa-1 B6-WT controls. Reduced tumor growth is associated with enhanced expansion of follicular T helper cells, germinal center B cells, and high titers of antitumor autoantibodies, which provoke robust antitumor immune responses in concert with tumor-specific cytolytic T cells. Analysis of tumor-infiltrating T cells revealed that the Qa-1 DK mutation was associated with an increase in the ratio of CD8(+) T effectors compared with CD8 Tregs. These data suggest that the CD8(+) T effector-Treg ratio may provide a useful prognostic index for cancer development and raise the possibility that depletion or inactivation of CD8 Tregs represents a potentially effective strategy to enhance antitumor immunity. (C) 2013 AACR.
引用
收藏
页码:207 / 216
页数:10
相关论文
共 38 条
[1]   Relevance of the tumor antigen in the validation of three vaccination strategies for melanoma [J].
Bellone, M ;
Cantarella, D ;
Castiglioni, P ;
Crosti, MC ;
Ronchetti, A ;
Moro, M ;
Garancini, MP ;
Casorati, G ;
Dellabona, P .
JOURNAL OF IMMUNOLOGY, 2000, 165 (05) :2651-2656
[2]   Decreased breast cancer risk in systemic lupus erythematosus: the search for a genetic basis continues [J].
Bernatsky, S. ;
Easton, D. F. ;
Dunning, A. ;
Michailidou, K. ;
Ramsey-Goldman, R. ;
Gordon, C. ;
Clarke, A. E. ;
Foulkes, W. .
LUPUS, 2012, 21 (08) :896-899
[3]   Systemic lupus and malignancies [J].
Bernatsky, Sasha ;
Kale, Mruganka ;
Ramsey-Goldman, Rosalind ;
Gordon, Caroline ;
Clarke, Ann E. .
CURRENT OPINION IN RHEUMATOLOGY, 2012, 24 (02) :177-181
[4]   Spatiotemporal Dynamics of Intratumoral Immune Cells Reveal the Immune Landscape in Human Cancer [J].
Bindea, Gabriela ;
Mlecnik, Bernhard ;
Tosolini, Marie ;
Kirilovsky, Amos ;
Waldner, Maximilian ;
Obenauf, Anna C. ;
Angell, Helen ;
Fredriksen, Tessa ;
Lafontaine, Lucie ;
Berger, Anne ;
Bruneval, Patrick ;
Fridman, Wolf Herman ;
Becker, Christoph ;
Pages, Franck ;
Speicher, Michael R. ;
Trajanoski, Zlatko ;
Galon, Jerome .
IMMUNITY, 2013, 39 (04) :782-795
[5]   Particularities of the vasculature can promote the organ specificity of autoimmune attack [J].
Binstadt, BA ;
Patel, PR ;
Alencar, H ;
Nigrovic, PA ;
Lee, DM ;
Mahmood, U ;
Weissleder, R ;
Mathis, D ;
Benoist, C .
NATURE IMMUNOLOGY, 2006, 7 (03) :284-292
[6]   An anti-double-stranded DNA monoclonal antibody induced by tumor cell-derived DNA inhibits the growth of tumor in vitro and in vivo via triggering apoptosis [J].
Cao, Qinghua ;
Xu, Wei ;
Wen, Zhenke ;
Xu, Lin ;
Li, Kang ;
Chu, Yiwei ;
Xiong, Sidong .
DNA AND CELL BIOLOGY, 2008, 27 (02) :91-100
[7]   Neutralizing Tumor-Promoting Chronic Inflammation: A Magic Bullet? [J].
Coussens, Lisa M. ;
Zitvogel, Laurence ;
Palucka, A. Karolina .
SCIENCE, 2013, 339 (6117) :286-291
[8]   VACCINATION WITH IRRADIATED TUMOR-CELLS ENGINEERED TO SECRETE MURINE GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR STIMULATES POTENT, SPECIFIC, AND LONG-LASTING ANTITUMOR IMMUNITY [J].
DRANOFF, G ;
JAFFEE, E ;
LAZENBY, A ;
GOLUMBEK, P ;
LEVITSKY, H ;
BROSE, K ;
JACKSON, V ;
HAMADA, H ;
PARDOLL, D ;
MULLIGAN, RC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (08) :3539-3543
[9]   Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives [J].
Ekström, K ;
Hjalgrim, H ;
Brandt, L ;
Baecklund, E ;
Klareskog, L ;
Ekbom, A ;
Askling, J .
ARTHRITIS AND RHEUMATISM, 2003, 48 (04) :963-970
[10]   Immunity, Inflammation, and Cancer [J].
Grivennikov, Sergei I. ;
Greten, Florian R. ;
Karin, Michael .
CELL, 2010, 140 (06) :883-899