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NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma.

ABSTRACT: Harnessing the immune adjuvant properties of natural killer T (NKT) cells is an effective strategy to generate anticancer immunity. The objective of this study was to increase the potency and durability of vaccine-induced immunity against B cell lymphoma by combining ?-galactosylceramide (?-GalCer)-loaded tumor cell vaccination with an agonistic antibody targeting the immune checkpoint molecule 4-1BB (CD137). We observed potent synergy when combining vaccination and anti-4-1BB antibody treatment resulting in significantly enhanced survival of mice harboring E?-myc tumors, including complete eradication of lymphoma in over 50% of mice. Tumor-free survival required interferon ? (IFN?)-dependent expansion of CD8(+) T cells and was associated with 4-1BB-mediated differentiation of KLRG1(+) effector CD8(+) T cells. 'Cured' mice were also resistant to lymphoma re-challenge 80 days later indicating successful generation of immunological memory. Overall, our results demonstrate that therapeutic anticancer vaccination against B cell lymphoma using an NKT cell ligand can be boosted by subsequent co-stimulation through 4-1BB leading to a sustainable immune response that may enhance outcomes to conventional treatment.

SUBMITTER: Kobayashi T

PROVIDER: S-EPMC4404843 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other

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NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma.

Kobayashi Takumi T Doff Brianna L BL Rearden Rory C RC Leggatt Graham R GR Mattarollo Stephen R SR

Oncoimmunology 20150107 3

Harnessing the immune adjuvant properties of natural killer T (NKT) cells is an effective strategy to generate anticancer immunity. The objective of this study was to increase the potency and durability of vaccine-induced immunity against B cell lymphoma by combining α-galactosylceramide (α-GalCer)-loaded tumor cell vaccination with an agonistic antibody targeting the immune checkpoint molecule 4-1BB (CD137). We observed potent synergy when combining vaccination and anti-4-1BB antibody treatment ...[more]

PMID: 25949907

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Project description:The reports on the origin of human CD8(+) Valpha24(+) T-cell receptor (TCR) natural killer T (NKT) cells are controversial. The underlying mechanism that controls human CD4 versus CD8 NKT cell development is not well-characterized. In the present study, we have studied total 177 eligible patients and subjects including 128 healthy latent Epstein-Barr-virus(EBV)-infected subjects, 17 newly-onset acute infectious mononucleosis patients, 16 newly-diagnosed EBV-associated Hodgkin lymphoma patients, and 16 EBV-negative normal control subjects. We have established human-thymus/liver-SCID chimera, reaggregated thymic organ culture, and fetal thymic organ culture. We here show that the average frequency of total and CD8(+) NKT cells in PBMCs from 128 healthy latent EBV-infected subjects is significantly higher than in 17 acute EBV infectious mononucleosis patients, 16 EBV-associated Hodgkin lymphoma patients, and 16 EBV-negative normal control subjects. However, the frequency of total and CD8(+) NKT cells is remarkably increased in the acute EBV infectious mononucleosis patients at year 1 post-onset. EBV-challenge promotes CD8(+) NKT cell development in the thymus of human-thymus/liver-SCID chimeras. The frequency of total (3% of thymic cells) and CD8(+) NKT cells ( approximately 25% of NKT cells) is significantly increased in EBV-challenged chimeras, compared to those in the unchallenged chimeras (<0.01% of thymic cells, CD8(+) NKT cells undetectable, respectively). The EBV-induced increase in thymic NKT cells is also reflected in the periphery, where there is an increase in total and CD8(+) NKT cells in liver and peripheral blood in EBV-challenged chimeras. EBV-induced thymic CD8(+) NKT cells display an activated memory phenotype (CD69(+)CD45RO(hi)CD161(+)CD62L(lo)). After EBV-challenge, a proportion of NKT precursors diverges from DP thymocytes, develops and differentiates into mature CD8(+) NKT cells in thymus in EBV-challenged human-thymus/liver-SCID chimeras or reaggregated thymic organ cultures. Thymic antigen-presenting EBV-infected dendritic cells are required for this process. IL-7, produced mainly by thymic dendritic cells, is a major and essential factor for CD8(+) NKT cell differentiation in EBV-challenged human-thymus/liver-SCID chimeras and fetal thymic organ cultures. Additionally, these EBV-induced CD8(+) NKT cells produce remarkably more perforin than that in counterpart CD4(+) NKT cells, and predominately express CD8alphaalpha homodimer in their co-receptor. Thus, upon interaction with certain viruses, CD8 lineage-specific NKT cells are developed, differentiated and matured intrathymically, a finding with potential therapeutic importance against viral infections and tumors.

Dataset Information

NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma.

Publications

NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma.

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