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Takashi Nishimura

Publications and source records attributed to Takashi Nishimura.

At least 37 records · Page 2Linked to original sources
PubMed2005

Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes.

Tumor antigen-specific CD4+ and CD8+ T lymphocytes, especially interferon-gamma (IFN-gamma)-producing type-1 helper T (Th1) and type-1 cytotoxic T (Tc1) cells, play a crucial role in tumor eradication. Adoptive transfer using tumor-specific Th1 and Tc1 cells is a promising therapeutic strategy for tumor immunotherapy. However, its clinical application has been hampered because of difficulties in generating tumor-specific Th1 cells from patients with tumors. To overcome this problem, we have developed an efficient method to prepare tumor-specific Th1 and Tc1 cells. T-cell receptor (TCR) alpha and beta genes obtained from an HLA-A24-restricted, Wilms tumor 1 (WT1) peptide-specific Tc clone were lentivirally transduced to polyclonally activated Th1 and Tc1 cells. As expected, TCR gene-modified Tc1 cells showed cytotoxicity and IFN-gamma production in response to peptide-loaded lymphoblastoid cell lines, WT1 gene-transduced cells, and freshly isolated leukemia cells expressing both WT1 and HLA-A24. Surprisingly, we further demonstrated that Th1 cells transduced with HLA-class I-restricted TCR genes also showed both cytotoxicity and cytokine production in an HLA-A24-restricted manner. In contrast to gene-modified Tc1 cells, Th1 cells produced high amounts of interleukin-2 (IL-2) in addition to IFN-gamma, which is beneficial for induction of antitumor cellular immunity. Thus, TCR gene-modified HLA-class I-restricted Th1 and Tc1 cells are a powerful strategy for the application to adoptive immunotherapy of human cancer.

Cytotoxicity, Immunologic↗
PubMed2005

PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1.

A polarity complex of PAR-3, PAR-6 and atypical protein kinase C (aPKC) functions in various cell-polarization events, including neuron specification. The small GTPase Cdc42 binds to PAR-6 and regulates cell polarity. However, little is known about the downstream signals of the Cdc42-PAR protein complex. Here, we found that PAR-3 directly interacted with STEF/Tiam1, which are Rac-specific guanine nucleotide-exchange factors, and that STEF formed a complex with PAR-3-aPKC-PAR-6-Cdc42-GTP. Cdc42 induces lamellipodia in a Rac-dependent manner in N1E-115 neuroblastoma cells. Disruption of Cdc42-PAR-6 or PAR-3-STEF binding inhibited Cdc42-induced lamellipodia but not filopodia. The isolated STEF-binding PAR-3 fragment was sufficient to induce lamellipodia independently of Cdc42 and PAR-6. PAR-3 is required for Cdc42-induced Rac activation, but is not essential for lamellipodia formation itself. In cultured hippocampal neurons, STEF accumulated at the tip of the growing axon and colocalized with PAR-3. The spatio-temporal activation and signalling of Cdc42-PAR-6-PAR-3-STEF/Tiam1-Rac seem to be involved in neurite growth and axon specification. We propose that the PAR-6-PAR-3 complex mediates Cdc42-induced Rac activation by means of STEF/Tiam1, and that this process seems to be required for the establishment of neuronal polarity.

Animals↗
PubMed2005

Immunosteroid as a regulator for Th1/Th2 balance: its possible role in autoimmune diseases.

Immune balance controlled by Th1 and Th2 cells is critical for the protection of host from pathogenic invasion while its imbalance becomes the cause of various immune disorders including autoimmune diseases. Cytokines, such as IL-12 and IL-4, are critical factor to drive the differentiation of naïve CD4(+) T cells to Th1 or Th2 cells. In addition to cytokines, steroid hormones have been demonstrated to affect on the control of Th1/Th2 balance and the onset of autoimmune diseases. Here, we will propose a new concept that immunosteroid, which is designated as a steroid produced by immunoregulatory cells, also play a critical role for regulation of Th1/Th2 balance. First example of immunosteroid is Th2-dependently produced progesterone. Th2 cells, but not Th1 cells expressed P450scc and 20alpha-HSD and produced progesterone from 22R-hydroxycholesterol in cooperation with 3beta-HSD-expressing mouse fibroblasts. Th2-dependently produced progesterone induced apoptotic cell death of Th1 cells and inhibited the differentiation of Th1 cells. While Th2 cells were escaped from toxic effect of progesterone by metabolizing it to non-toxic 20alpha-hydroxyprogesterone with 20alpha-HSD. Second example of immunosteroid is dendritic cell (DC)-dependently produced 1alpha,25-dihydroxyvitamin D3 [1,25(OH)(2)D] secosteroid hormone, which has been demonstrated to inhibit autoimmune diseases. We found that 25-hydroxyvitamin D3 1alpha-hydroxylase, which metabolize 25-hydroxyvitamin D3 (inactive form) to 1,25(OH)(2)D was expressed in Th2-cytokine induced bone marrow-derived DC2 but not Th1-cytokine induced DC1. Moreover, 1,25(OH)(2)D was significantly inhibited DC1-induced type1 immunity. Thus, we initially demonstrated the critical role of immunosteroids in the control of Th1/Th2 balance influencing on the onset of autoimmune diseases. Therefore, it will be an important issue to investigate the possible role of immunosteroids for the regulation of autoimmune diseases.

Animals↗
PubMed2005

[Development of DNA array filter useful for the analysis of Th1/Th2 balance].

DNA arrays are useful for determining the expression levels of a number of genes at once. We utilized this technique to evaluate the Th1/Th2 balance in vivo. Immune responses are controlled by two types of helper T cells, Th1 and Th2. Once the balance of Th1/Th2 immunity is disrupted, various immune diseases can develop. Thus, it is important to evaluate the Th1/Th2 balance in each patient for diagnosis, treatment and/or prophylaxis of immune diseases. We have identified a number of genes specifically expressed in Th1 or Th2 cells, and developed a DNA array filter spotted with these genes. We confirmed that this filter is useful for the evaluation of changes in the immune balance in vivo. Clinical application of this technology may lead to the tailor-made therapy of immune diseases through the evaluation of the immune balance in each patient.

Actins↗
PubMed2005

Natural killer cells play a role in MHC class I in vivo induction in tumor cells that are MHC negative in vitro.

The natural killer (NK) cell is one of the key cells in discriminating major histocompatibility complex (MHC) negative 'missing-self' target tumor cells, and interleukin 2 (IL-2) treatment was effective in inducing NK cell activation. In this study, we tried to clarify how poorly-immunogenic murine B16 melanoma could be discriminated in vivo by creating an IL-2 cDNA-transduced immunogene therapy model (B16/IL-2). In vitro study showed that IL-2 introduction did not induce MHC class I. However, immune cells depleted total tumor digest, which consisted of 90% anti-melanoma MM2-9B6-positive cells that revealed B16/IL-2 strongly, and control tumor cells (B16/mock) partially expressed MHC class I in vivo. In the B16/IL-2 model, NK cell infiltration was 10 times higher than B16/mock (7.6 versus 0.73, p=0.017). In addition, the cell surface of CD69-expressing NK cell population was increased in B16/IL-2, and the interferon gamma (IFNgamma) message level in NK cells was significantly increased in B16/IL-2 (p=0.0359). Interestingly, NK cell depletion in vivo completely abolished MHC class I expression on B16/mock, and decreased MHC class I expression and T-cell infiltration in B16/IL-2. These data suggest that NK cells are not only important for missing-self recognition, but are also crucial for induction of tumor cell MHC molecule expression and play an important role in helping acquired immunity to recognize tumor cells.

Animals↗
PubMed2004

Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity.

Unmethylated cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs) exhibit potent immunostimulating activity by binding with Toll-like receptor 9 (TLR9) expressed on antigen-presenting cells. Here, we show that CpG-ODN encapsulated in cationic liposomes (CpG-liposomes) improves its incorporation into CD11c(+) dendritic cells (DCs) and induces enhanced serum interleukin (IL)-12 levels compared with unmodified CpG-ODN. CpG-liposome potently activated natural killer (NK) cells (84.3%) and NKT cells (48.3%) to produce interferon-gamma (IFN-gamma), whereas the same dose of unmodified CpG-ODN induced only low numbers of IFN-gamma-producing NK cells (12.7%) and NKT cells (1.6%) to produce IFN-gamma. In contrast with the NKT cell agonist alpha-galactosylceramide, which induces both IFN-gamma and IL-4 production by NKT cells, CpG-liposome only induced IFN-gamma production by NKT cells. Such potent adjuvant activities of CpG-liposome were absent in TLR9-deficient mice, indicating that CpG-liposome was as effective as CpG-ODN in stimulating type 1 innate immunity through TLR9. In addition to TLR9, at least two other factors, IL-12 production by DCs and direct contact between DCs and NK or NKT cells, were essential for inducing type 1 innate immunity by CpG-liposome. Furthermore, ligation of TLR9 by CpG-liposome coencapsulated with ovalbumin (OVA) caused the induction of OVA-specific CTLs, which exhibited potent cytotoxicity against OVA-expressing tumor cells. These results indicate that CpG-liposome alone or combined with tumor antigen protein provides a promising approach for the prevention or therapy of tumors.

Adjuvants, Immunologic↗
PubMed2004

STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation.

When wild-type BALB/c mice were transferred with OVA-specific Th2 cells followed by OVA inhalation, a severe eosinophilia, mucus hypersecretion and airway hyper-responsiveness (AHR) was induced in parallel with a marked elevation of IL-4, IL-5 and IL-13 levels in bronchoalveolar lavage fluid (BALF). However, neither eosinophilia, AHR nor mucus hypersecretion was induced in Th2 cell-transferred STAT6-/- mice. The failure of eosinophilia was not due to the defect of Th2 cytokine production in BALF of STAT6-/- mice transferred with Th2 cells, but because of the defect of STAT6-dependent eotaxin production. Indeed, intranasal administration of eotaxin reconstituted pulmonary eosinophilia but not AHR and mucus hypersecretion in OVA-inhalated STAT6-/- mice. These results initially provided direct evidence that STAT6-dependent eotaxin production is essential for pulmonary eosinophilia. We also dissociated the role of STAT6 for eosinophilia from that for AHR and mucus hypersecretion. Thus, STAT6 also plays a critical role at late phase of Th2-dependent allergy induction.

Administration, Intranasal↗
PubMed2004

NKT cells act as regulatory cells rather than killer cells during activation of NK cell-mediated cytotoxicity by alpha-galactosylceramide in vivo.

Administration of NKT cell ligands, alpha-galactosylceramide (alpha-GalCer) resulted in the activation of both cytokine production and natural killing. These responses were abolished in both CD1d-deficient mice and Valpha14NKT-deficient mice. Therefore, NKT cells have been considered to be responsible cells for both cytokine production and natural killing. Here, we reevaluated a critical role of NKT and NK cells at early time after alpha-GalCer administration. Intracellular staining experiments demonstrated that NKT cells were the earliest source of both IL-4 and IFN-gamma production after alpha-GalCer administration in vivo. However, these alpha-GalCer-activated NKT cells exhibited no significant natural killing activity. In contrast, isolated NK1.1+CD3- classical NK cells exhibited greatly enhanced natural killing activity 6 h after alpha-GalCer administration. NKT cells, however, exhibited a strong cytotoxicity when they were activated and expanded with alpha-GalCer plus IL-2 in vitro. These results indicated that NKT cells act as regulatory cells via production of cytokines for activation of NK cell-mediated cytotoxicity in vivo at early phase after alpha-GalCer administration. Thus, NK cells rather than NKT cells may be a crucial early activated killer induced by alpha-GalCer in vivo.

Animals↗
PubMed2004

Unexpected role of TNF-alpha in graft versus host reaction (GVHR): donor-derived TNF-alpha suppresses GVHR via inhibition of IFN-gamma-dependent donor type-1 immunity.

Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation, leading to significant morbidity and mortality. Host-derived TNF-alpha play a role in the induction of allo-reactive donor T cell activation and the pathogenesis of GVHD. On the other hand, the precise role of donor-derived TNF-alpha in GVHD remains unclear. To elucidate this issue, we designed an acute GVHD model using (B6 x D2) F1 recipient mice transferred with spleen cells derived from either wild-type or TNF-alpha(-/-) C57BL/6 mice. Surprisingly, we found that spleen cells from TNF-alpha(-/-) mice induce more severe graft versus host reaction (GVHR) than wild-type spleen cells upon transfer into B6D2F1 mice. Transplantation of TNF-alpha(-/-) mouse spleen cells was associated with enhanced anti-host CTL generation and augmented deletion of host cells. Moreover, mice receiving TNF-alpha(-/-) cells showed significantly higher levels of serum IFN-gamma, which was mainly produced by donor CD8+ T cells. We also demonstrated that TNF-alpha deficiency in donor spleen cells caused a marked elevation of TNF-alpha producing capacity by LPS-stimulated host macrophages. Such enhanced GVHR was completely prevented by using TNF-alpha(-/-)IFN-gamma(-/-) splenic cells. Our findings demonstrate, for the first time, that donor-derived TNF-alpha suppress GVHR by inhibiting IFN-gamma-dependent donor type-1 immunity which is essential for host TNF-alpha elevation.

Animals↗
PubMed2004

Generation of leukemia-specific T-helper type 1 cells applicable to human leukemia cell-therapy.

Leukemic dendritic cells (DC) were induced from the peripheral blood (PB) or bone marrow (BM) of leukemia patients by culture with (i) GM-CSF + IL-3 (neutral condition); (ii) GM-CSF + IL-3 + IL-12 + IFN-gamma (type 1-condition); or (iii) GM-CSF + IL-3 + IL-4 (type 2-condition). Although leukemic cells rapidly differentiated into adhesive leukemic DC in all culture conditions, type1-conditions were the most suitable for inducing leukemic DC expressing high levels of HLA and costimulatory molecules. Addition of IL-2 after 2 days of culture induced a preferential growth of minor T cell populations interacting with leukemic DC. In particular, IFN-gamma-producing CD4+ Th1 cells were efficiently expanded in type 1 culture conditions but nor in neutral or type 2-conditions. However, CD4+ T cells expanded in neutral conditions showed Th1-like functions if they were pulsed with IFN-gamma for 2 days before harvest. Such Th1 cells produced IFN-gamma and exhibited cytotoxicity in response to autologous leukemia cells. We further demonstrated that IFN-gamma production of leukemia-specific Th1 cells was blocked by anti-HLA-DR mAb. Thus, we established a novel culture system for inducing leukemia-specific Th1 cells.

Adult↗
PubMed2004

Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity.

Neurons polarize to form elaborate multiple dendrites and one long axon. The establishment and maintenance of axon/dendrite polarity are fundamentally important for neurons. Recent studies have demonstrated that the polarity complex PAR-3-PAR-6-atypical protein kinase C (aPKC) is involved in polarity determination in many tissues and cells. The function of the PAR-3-PAR-6-aPKC protein complex depends on its subcellular localization in polarized cells. PAR-3 accumulates at the tip of growing axons in cultured rat hippocampal neurons, but the molecular mechanism of this localization remains unknown. Here we identify a direct interaction between PAR-3 and KIF3A, a plus-end-directed microtubule motor protein, and show that aPKC can associate with KIF3A through its interaction with PAR-3. The expression of dominant-negative PAR-3 and KIF3A fragments that disrupt PAR-3-KIF3A binding inhibited the accumulation of PAR-3 and aPKC at the tip of the neurites and abolished neuronal polarity. These results suggest that PAR-3 is transported to the distal tip of the axon by KIF3A and that the proper localization of PAR-3 is required to establish neuronal polarity.

Animals↗
PubMed2004

Generation and targeting of human tumor-specific Tc1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor.

CD4+ Th cells, in particular IFN-gamma-producing Th1 cells, play a critical role in the activation and maintenance of Tc1 cells that are essential for tumor eradication. Here, we report the generation of artificial tumor-specific Th1 and Tc1 cells from nonspecifically activated T cells using a lentiviral transduction system. Anti-CD3-activated T cells from healthy human donors were transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor gene composed of single-chain variable fragments derived from an anticarcinoembryonic antigen (CEA)-specific monoclonal antibody fused to an intracellular signaling domain derived from the cytoplasmic portions of membrane-bound CD28 and CD3zeta. These artificial tumor-specific Tc1 and Th1 cells, termed Tc1- and Th1-T bodies, respectively, could be targeted to CEA+ tumor cells independently of MHC restriction. Specifically, Tc1-T bodies demonstrated high cytotoxicity and produced IFN-gamma in response to CEA+ tumor cell lines but not CEA- tumors. Although Th1-T bodies exhibited low cytotoxicity, they secreted high levels of IFN-gamma and interleukin-2 in response to CEA+ tumor cells. Such CEA+ tumor-specific activation was not observed in mock gene-transduced nonspecific Tc1 and Th1 cells. Moreover, Tc1- and Th1-T bodies exhibited strong antitumor activities against CEA+ human lung cancer cells implanted into RAG2(-/-) mice. Furthermore, combined therapy with Tc1- and Th1-T bodies resulted in enhanced antitumor activities in vivo. Taken together, our findings demonstrate that Tc1- and Th1-T bodies represent a promising alternative to current methods for the development of effective adoptive immunotherapies.

Animals↗
PubMed2004

IFN-gamma-induced SOCS-1 regulates STAT6-dependent eotaxin production triggered by IL-4 and TNF-alpha.

The production of eotaxin, which is a critical mediator for airway inflammation, is inhibited by IFN-gamma. Here, we investigated the precise mechanisms underlying IFN-gamma-dependent inhibition of eotaxin production using mouse embryonic fibroblasts (MEF). MEF produced high levels of eotaxin in STAT6-dependent manner when they were cultured with both IL-4 and TNF-alpha. However, the eotaxin production by MEF was strongly inhibited by addition of IFN-gamma. Western-blotting analysis demonstrated that IFN-gamma downmodulated STAT6 phosphorylation induced by IL-4 and TNF-alpha. Moreover, IFN-gamma did not exhibit its inhibitory effect on both STAT6-phosphorylation and eotaxin production in MEF obtained from deficient mice in STAT1, a key molecule of IFN-gamma signaling. We also demonstrated that SOCS-1, a potent inhibitory molecule of IL-4 signaling, was induced by IFN-gamma in STAT1-dependent manner. This indicated that SOCS-1 might be involved in IFN-gamma-mediated STAT1-dependent inhibition of eotaxin production. In SOCS-1(-/-) MEF, IFN-gamma inhibited neither STAT6 phosphorylation nor eotaxin production induced by IL-4 and TNF-alpha. Conversely, retroviral transduction of SOCS-1 into MEF inhibited STAT6 phosphorylation and eotaxin production induced by IL-4 and TNF-alpha, in the absence of IFN-gamma. Thus, we demonstrated that IFN-gamma-induced inhibition of STAT6 phosphorylation and eotaxin production were mediated by SOCS-1 induced in STAT1-dependent manner.

Animals↗
PubMed2004

Potentiation of tumor eradication by adoptive immunotherapy with T-cell receptor gene-transduced T-helper type 1 cells.

Adoptive immunotherapy using antigen-specific T-helper type 1 (Th1) cells has been considered as a potential strategy for tumor immunotherapy. However, its application to tumor immunotherapy has been hampered by difficulties in expanding tumor-specific Th1 cells from tumor-bearing hosts. Here, we have developed an efficient protocol for preparing mouse antigen-specific Th1 cells from nonspecifically activated Th cells after retroviral transfer of T-cell receptor (TCR)-alpha and TCR-beta genes. We demonstrate that Th1 cells transduced with the TCR-alpha and -beta genes from the I-A(d)-restricted ovalbumin (OVA)(323-339)-specific T-cell clone DO11.10 produce IFN-gamma but not interleukin-4 in response to stimulation with OVA(323-339) peptides or A20 B lymphoma (A20-OVA) cells expressing OVA as a model tumor antigen. TCR-transduced Th1 cells also exhibited cytotoxicity against tumor cells in an antigen-specific manner. Moreover, adoptive transfer of TCR-transduced Th1 cells, but not mock-transduced Th1 cells, exhibited potent antitumor activity in vivo and, when combined with cyclophosphamide treatment, completely eradicated established tumor masses. Thus, TCR-transduced Th1 cells are a promising alternative for the development of effective adoptive immunotherapies.

Animals↗
PubMed2004

Glucose-insulin-potassium solution improves left ventricular energetics in chronic ovine diabetes.

BACKGROUND: Therapeutic modulation of myocardial metabolism improves outcomes in diabetic patients following myocardial infarction and coronary artery surgery. However, the mechanism of this beneficial effect has not been fully elucidated. This study evaluated the effect of glucose-insulin-potassium solution (GIK) on left ventricular (LV) energetics and oxygen utilization efficiency in a chronic ovine model of diabetes. METHODS: Diabetes was induced in sheep with streptozotocin. Experiments were performed following 12 months untreated diabetes (n = 6) and in controls (n = 6). Open-chest anesthetized sheep were instrumented to determine the LV pressure-volume relationship, oxygen consumption, and free fatty acid uptake. Glucose-insulin-potassium was infused at 1.5 mL x kg(-1) x h(-1) for 60 minutes and assessment repeated. RESULTS: Glucose-insulin-potassium decreased LV free fatty acid uptake in control: 0.090 +/- 0.047 microg/beat/100 g to 0.024 +/- 0.022 microg/beat/100 g, p = 0.02 and diabetes: 0.33 +/- 0.32 microg/beat/100 g to 0.11 +/- 0.13 microg/beat/100 g, p = 0.04. Similarly, GIK decreased unloaded left ventricular oxygen consumption (LVVO(2)) in both control (0.42 +/- 0.05 to 0.37 +/- 0.13J/beat/100 g, p < 0.001) and diabetic sheep (0.40 +/- 0.24 to 0.23 +/- 0.23J/beat/100 g, p < 0.001). The slope of the LVVO(2)-pressure-volume area relation (contractile efficiency) was unchanged in either group. Glucose-insulin-potassium improved LV contractility 58% +/- 37% (p = 0.005) and stroke work efficiency 18% +/- 10% (p = 0.009) in diabetic animals but not controls. Therefore, oxygen utilization efficiency (stroke work-LVVO(2)) increased only in diabetic animals (16.6% +/- 4.8% to 26.9% +/- 3.6%, p = 0.002) following GIK. CONCLUSIONS: This study provides in vivo evidence that GIK improves LV energetics in diabetes. Oxygen utilization efficiency is improved as a result of improved stroke work efficiency and decreased unloaded LVVO(2). Improved efficiency of oxygen utilization provides a physiologic rationale for the beneficial effect of GIK in diabetic patients.

Animals↗
PubMed2004

The critical role of type-1 innate and acquired immunity in tumor immunotherapy.

The discovery of a large array of tumor antigens has demonstrated that host lymphocytes can indeed recognize and destroy tumor cells as originally proposed in the cancer immunosurveillance hypothesis. Recent reports that led to the cancer immunoediting concept also strongly support the immunosurveillance hypothesis, and they further indicate that the host immune system plays a critical role not only in promoting host protection against cancer but also in selecting tumors that can better escape from immune attack. Thus, it is now clear that T cells have the ability to recognize and destroy spontaneously arising tumors. However, the generation of antitumor immunity is often difficult in the tumor-bearing host because of various negative regulatory mechanisms. Here, we review our recent work on tumor immunotherapy, which utilizes the activation of type-1 innate and/or acquired immunity as a potent strategy to overcome immunosup-pression in the tumor-bearing host. We have established a variety of tumor therapeutic protocols that aim to activate type-1 immunity, such as tumor-vaccine therapy with CpG encapsulat-ed in liposomes, cell therapy using tumor-specific Th1 cells, and gene therapy using gene-engineered Th1 cells. We found that CpG encapsulated in liposomes stimulated IL-12-producing DC and induced IFN-gamma-producing NK cells, NKT cells, and tumor-specific CTL. Th1 cell therapy was also shown to be beneficial for acceleration of APC/Th1 cell-cell interaction in the DLN, which was critical for inducing tumor-specific CTL at the tumor site. Therefore, we conclude that the activation of type-1 innate and acquired immunity is crucial for tumor immunotherapy in order to overcome strong immunosuppression in the tumor-bearing host.

Animals↗