Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy

Yamasaki, Kazuki; Horiguchi, Susumu; Kurosaki, Motoyoshi; Kunii, Naoki; Nagato, Kaoru; Hanaoka, Hideki; Shimizu, Naomi; Ueno, Naoyuki; Yamamoto, Seiji; Taniguchi, Masaru; Motohashi, Shinichiro; Nakayama, Toshinori; Okamoto, Yoshitaka

doi:10.1016/j.clim.2010.11.014

Cited by 159 publications

(134 citation statements)

References 25 publications

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“…Dollar symbol WT Cis + α-GC vs KO Cis + α-GC; WT Cis vs KO Cis + α-GC chemotherapy. Several clinical trials using α-GC are currently ongoing for different types of cancers worldwide [21,[27][28][29]. However, there have been limited studies on α-GC in pre-clinical models or in patients with mesothelioma.…”

Section: Discussionmentioning

confidence: 99%

Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma

Yun

Tagawa

et al. 2014

Cancer Immunol Immunother

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We studied the impact of natural killer T (NKT) cell activation by alpha-galactocysylceramide (α-GalCer, α-GC) on cancer cell repopulation during chemotherapy in murine mesothelioma. The number of NKT cells was found to be increased during the development of murine mesothelioma. NKT cells specifically recognize α-GC through CD1d resulting in their activation and expansion. Tumor-bearing mice were treated with chemotherapy once weekly, and α-GC was followed after each cycle of chemotherapy. Anti-tumor effect was evaluated on wild-type (WT) and CD1d knockout (CD1dKO) mice. Cancer cell proliferation and apoptosis were evaluated by Ki67 and TUNEL immunohistochemistry. CD4(+) and CD8(+) T cell proportion and activation in tumor, spleen, draining lymph node and peripheral blood were determined by flow cytometry, and gene expression of activated T cell-related cytokines was quantified by reverse transcription PCR. NKT cells were identified by CD1d-α-GC-tetramer staining. In WT mice, tumor growth delay was achieved by cisplatin (Cis), and this effect was improved in combination with α-GC, but α-GC alone had little effect. Cancer cell proliferation during chemotherapy was significantly inhibited by α-GC, while cancer cell death was significantly upregulated. α-GC following chemotherapy resulted in NKT cell expansion and an increase of interferon-γ production in the draining lymph node, blood and spleen. Gene expression of immune-associated cytokines was upregulated. Strikingly, the percentage of inducible T cell co-stimulator(+)CD4 T cells, Th17/Tc17 cells increased in splenocytes. In CD1d KO mice, however, Cis alone was less effective and Cis + α-GC provided no additional benefit over Cis alone. α-GC alone had minimal effect in both mice. NKT activation between cycles of chemotherapy could improve the outcome of mesothelioma treatment.

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Section: Discussionmentioning

confidence: 99%

Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma

Yun

Tagawa

et al. 2014

Cancer Immunol Immunother

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“…The potential importance of NKTs for tumor immunity and immunotherapy has been demonstrated in multiple models of cancer in mice and in early-stage clinical trials in cancer patients (5)(6)(7)(8)(9)(10). In contrast to T cells, NKTs effectively traffic to the tumor site and can mediate antitumor responses via either direct killing of CD1d + tumor cells, inhibition of tumor-supportive macrophages, or transactivation of NK cells (11).…”

Section: Introductionmentioning

confidence: 99%

CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo

Tian¹,

Courtney²,

Jena³

et al. 2016

Journal of Clinical Investigation

143

165

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“…In the past 2 decades, a series of iNKT cellbased clinical trials have been conducted, mainly targeting cancer (4,21). A recent trial reported encouraging antitumor immunity in patients with head and neck squamous cell carcinoma, attesting to the potential of iNKT cell-based immunotherapies (22). However, most trials yielded unsatisfactory results (4,21).…”

Section: Discussionmentioning

confidence: 99%

Genetic engineering of hematopoietic stem cells to generate invariant natural killer T cells

Smith

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Invariant natural killer T (iNKT) cells comprise a small population of αβ T lymphocytes. They bridge the innate and adaptive immune systems and mediate strong and rapid responses to many diseases, including cancer, infections, allergies, and autoimmunity. However, the study of iNKT cell biology and the therapeutic applications of these cells are greatly limited by their small numbers in vivo (∼0.01-1% in mouse and human blood). Here, we report a new method to generate large numbers of iNKT cells in mice through T-cell receptor (TCR) gene engineering of hematopoietic stem cells (HSCs). We showed that iNKT TCR-engineered HSCs could generate a clonal population of iNKT cells. These HSC-engineered iNKT cells displayed the typical iNKT cell phenotype and functionality. They followed a two-stage developmental path, first in thymus and then in the periphery, resembling that of endogenous iNKT cells. When tested in a mouse melanoma lung metastasis model, the HSC-engineered iNKT cells effectively protected mice from tumor metastasis. This method provides a powerful and high-throughput tool to investigate the in vivo development and functionality of clonal iNKT cells in mice. More importantly, this method takes advantage of the self-renewal and longevity of HSCs to generate a long-term supply of engineered iNKT cells, thus opening up a new avenue for iNKT cell-based immunotherapy. αβ T lymphocytes highly conserved from mice to humans. Like conventional αβ T cells, iNKT cells are derived from hematopoietic stem cells (HSCs) and develop in the thymus. However, they differ from conventional T cells in several important aspects, including their display of NK cell markers, their recognition of glycolipid antigens presented by the nonclassical monomorphic major histocompatibility complex (MHC) molecule CD1d, and their expression of semi-invariant T-cell receptors (identical α chains paired with a limited selection of β chains) (1, 2). Despite their small numbers in vivo (∼0.1-1% in mouse blood and ∼0.01-1% in human blood), iNKT cells have been suggested to play important roles in regulating many diseases, including cancer, infections, allergies, and autoimmunity (3). When stimulated, iNKT cells rapidly release a large amount of effector cytokines like IFN-γ and IL-4, both as a cell population and at the single-cell level. These cytokines then activate various immune effector cells, such as natural killer (NK) cells and dendritic cells (DCs) of the innate immune system, as well as CD4 helper and CD8 cytotoxic conventional αβ T cells of the adaptive immune system via activated DCs (3, 4). Because of their unique activation mechanism, iNKT cells can attack multiple diseases independent of antigen and MHC restrictions, making them attractive universal therapeutic agents (3, 4). Notably, because of the capacity of effector NK cells and conventional αβ T cells to specifically recognize diseased tissue cells, iNKT cell-induced immune reactions result in limited off-target side effects (3, 4).Restricted by their extremely low numbers, ...

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Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy

Cited by 159 publications

References 25 publications

Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma

Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma

CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo

Genetic engineering of hematopoietic stem cells to generate invariant natural killer T cells

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