A combined local treatment with anti-PD-1 antibody and bone marrow derived dendritic cells after x-ray irradiation to subcutaneous melanoma in a murine model.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14541-e14541
Author(s):  
Yuzi Wang ◽  
Lue Sun ◽  
Xiaokang Li ◽  
Koji Tsuboi
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Combination Treatment ◽  
Bone Marrow Cells ◽  
Local Treatment ◽  
Activated T Cells ◽  
X Ray

e14541 Background: In situ dying and just died tumor cells after irradiation give danger signals and release tumor-specific antigens which are supposed to be incorporated into dendritic cells (DCs), and sequentially rendering T-cells activated and proliferated. However, it has been clarified that activated T-cells are killed by PD-L1 ligands on tumor cells which bind to PD-1 receptors on T-cells, consequently suppressing systemic cellular immunological response. To improve local control and prevent metastases after localized radiotherapy, we examined whether the combination of anti-PD-1 antibody and bone marrow derived DCs (BM-DCs) can enhance both the local and systemic antitumor immunoreactions after localized X-ray irradiation in a murine melanoma model. Methods: BM-DCs were induced by using GM-CSF and IL-4 from bone marrow cells taken from the femur and tibia of C57BL/6 mice. Syngeneic B16 melanoma cells implanted subcutaneously at the left thighs of C57BL/6 mice were irradiated with X-ray (8 Gy) 5 days after inoculation. After 1, 3, 5, 7 days from irradiation, induced DCs were injected directly to the tumor site, similarly, after 1, 3, 5 days from irradiation, anti-PD-1 antibody were injected intraperitoneally. To examine the systemic immunoreaction, B16 cells were also inoculated to the right side 4 days after the left side inoculation, and treated with the same protocols only on the left side. The size of tumors was monitored and survival analyses were performed. Results: The induced DCs showed the ability to incorporate antigens and to prime and proliferate T-cells in vitro. The combination treatment of anti-PD-1 antibody, BM-DCs and X-ray irradiation showed a significant delay of tumor growth compared to single or double combination treatments in vivo. In addition, this triple combination treatment significantly inhibited the tumor growth on the other side compared to other treatments. Conclusions: DCs and anti-PD-1 antibody significantly enhanced the antitumor effect of X-ray irradiation and prolonged the survival time. This combination also can induce a strong systemic antitumor immunoreaction which could treat metastatic tumors.

Activated Dendritic Cells From Bone Marrow Cells of Mice Receiving Cytokine-Expressing Tumor Cells Are Associated With the Enhanced Survival of Mice Bearing Syngeneic Tumors

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4328-4335
Author(s):  
Shin-ichiro Fujii ◽  
Hirofumi Hamada ◽  
Koji Fujimoto ◽  
Taizo Shimomura ◽  
Makoto Kawakita
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Cells ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Interleukin 4 ◽  
Gm Csf ◽  
Tumor Bearing ◽  
Macrophage Colony

Dendritic cells (DCs), which phagocytose antigens and subsequently proliferate and migrate, may be the most powerful antigen-presenting cells that activate naive T cells. To determine their role in the immune response to tumors, we used WEHI-3B murine leukemia cells transduced with adenovirus vectors expressing cytokines. We found that mixtures of irradiated cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) plus those expressing interleukin-4 (IL-4) or tumor necrosis factor  (TNF) protected mice against WEHI-3B–induced leukemias. When bone marrow mononuclear cells (BMMNCs) obtained from mice that had been injected with irradiated, cytokine-expressing tumor cells were injected into tumor-bearing mice, the survival of the latter was significantly prolonged; the longest survival was observed in mice receiving BMMNCs containing an increased number of DCs from animals injected with a mixture of tumor cells expressing GM-CSF with those expressing IL-4. Assay for antileukemic effects in spleen of the latter animals showed specific antitumor cytotoxicity against WEHI-3B, suggesting that DCs from donor mice activate specific T cells in the tumor-bearing recipients. These results suggest that the infusion of syngeneic BMMNCs stimulated with cytokine-expressing tumor cells may be effective in treating certain types of tumors.

Activated Dendritic Cells From Bone Marrow Cells of Mice Receiving Cytokine-Expressing Tumor Cells Are Associated With the Enhanced Survival of Mice Bearing Syngeneic Tumors

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4328-4335 ◽  
Author(s):  
Shin-ichiro Fujii ◽  
Hirofumi Hamada ◽  
Koji Fujimoto ◽  
Taizo Shimomura ◽  
Makoto Kawakita
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Cells ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Interleukin 4 ◽  
Gm Csf ◽  
Tumor Bearing ◽  
Macrophage Colony

Abstract Dendritic cells (DCs), which phagocytose antigens and subsequently proliferate and migrate, may be the most powerful antigen-presenting cells that activate naive T cells. To determine their role in the immune response to tumors, we used WEHI-3B murine leukemia cells transduced with adenovirus vectors expressing cytokines. We found that mixtures of irradiated cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) plus those expressing interleukin-4 (IL-4) or tumor necrosis factor  (TNF) protected mice against WEHI-3B–induced leukemias. When bone marrow mononuclear cells (BMMNCs) obtained from mice that had been injected with irradiated, cytokine-expressing tumor cells were injected into tumor-bearing mice, the survival of the latter was significantly prolonged; the longest survival was observed in mice receiving BMMNCs containing an increased number of DCs from animals injected with a mixture of tumor cells expressing GM-CSF with those expressing IL-4. Assay for antileukemic effects in spleen of the latter animals showed specific antitumor cytotoxicity against WEHI-3B, suggesting that DCs from donor mice activate specific T cells in the tumor-bearing recipients. These results suggest that the infusion of syngeneic BMMNCs stimulated with cytokine-expressing tumor cells may be effective in treating certain types of tumors.

Bone marrow microenvironment controls the in vivo differentiation of murine dendritic cells into osteoclasts

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 5074-5083 ◽  
Author(s):  
Abdelilah Wakkach ◽  
Anna Mansour ◽  
Romain Dacquin ◽  
Emmanuel Coste ◽  
Pierre Jurdic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bone Cells ◽  
Activated T Cells

Abstract Finding that activated T cells control osteoclast (OCL) differentiation has revealed the importance of the interactions between immune and bone cells. Dendritic cells (DCs) are responsible for T-cell activation and share common precursors with OCLs. Here we show that DCs participate in bone resorption more directly than simply through T-cell activation. We show that, among the splenic DC subsets, the conventional DCs have the higher osteoclastogenic potential in vitro. We demonstrate that conventional DCs differentiate into functional OCLs in vivo when injected into osteopetrotic oc/oc mice defective in OCL resorptive function. Moreover, this differentiation involves the presence of activated CD4+ T cells controlling a high RANK-L expression by bone marrow stromal cells. Our results open new insights in the differentiation of OCLs and DCs and offer new basis for analyzing the relations between bone and immune systems.

scholarly journals Normal Regulatory α/β T Cells Effectively Eliminate Abnormally Activated T Cells Lacking the Interleukin 2 Receptor β in Vivo

1999 ◽  
Vol 190 (11) ◽  
pp. 1561-1572 ◽  
Author(s):  
Haruhiko Suzuki ◽  
Yan Wen Zhou ◽  
Masashi Kato ◽  
Tak W. Mak ◽  
Izumi Nakashima
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Fas Ligand ◽  
Bone Marrow Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Receptor System

Although interleukin 2 (IL-2) has been thought to be the most important cytokine for T cell growth, animals lacking IL-2 or a component of its receptor molecules have more expanded T cells with activated memory phenotype, indicating an indispensable role for the IL-2/IL-2 receptor system in regulating the size and activity of the T cell population. In this study, we investigated the possible mechanism of abnormal expansion of activated T cells in IL-2 receptor β chain (IL-2Rβ)−/− mice using the systems of bone marrow transplantation and T cell transfer. Here, we show that IL-2Rβ2/− T cells in mice reconstituted with a mixture of IL-2Rβ2/− and IL-2Rβ1/+ bone marrow cells did not develop into an abnormally activated stage, and that already activated IL-2Rβ2/− T cells were effectively eliminated by IL-2Rβ1/+ T cells when both cells were cotransferred to T cell–deficient host mice. This regulation and/or elimination was dependent on T cells bearing α/β type T cell receptor, especially on CD8+ T cells and independent of the Fas–Fas ligand (FasL) system. IL-2Rβ1/+ T cells that eliminated activated IL-2Rβ2/− T cells expressed FasL, perforin, granzyme B, and tumor necrosis factor α/β. These results indicate a novel function of IL-2Rβ that is necessary for the induction of regulatory T cells acting to eliminate activated T cells.

Sequential Blockade and Engagement of Co-Stimulatory Pathways: A Potential Strategy for Amplifying Graft-Versus-Leukemia Responses without GVHD.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3075-3075
Author(s):  
Ronjon Chakraverty ◽  
Jennifer Buchli ◽  
Guiling Zhao ◽  
Richard Hsu ◽  
Michael Croft ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cd8 T Cells ◽  
Bone Marrow Cells ◽  
Host Cells ◽  
Effector Memory ◽  
Activated T Cells ◽  
Class I Mhc ◽  
Graft Versus Leukemia ◽  
Ctl Activity

Abstract One potential approach for the effective disengagement of graft-versus-leukemia (GVL) effects from graft-versus-host disease (GVHD) following BMT is the use of nonmyeloablative conditioning as a platform for the adoptive transfer of donor T cells. In pre-clinical models, donor CD8+ T cells can induce powerful responses against tumors of host origin, but the effect lacks durability such that a re-challenge with tumor inevitability leads to tumor progression and death. This deficit is associated with the failure of functional CD8+ effector/memory T cells (TE/M) to survive long-term post-DLI. To examine the fate of GVH-reactive CD8+ T cells following DLI, we established mixed hematopoietic chimeras (MC) in a parent →F1 model using a nonmyeloablative protocol that incorporates co-stimulatory molecule blockade. B6D2F1 mice received 3Gy TBI and intra-peritoneal injections of anti-CD154 and anti-CD8 mAb on day 0 followed by infusion of 2 x 107 C57BL/6 bone marrow cells. 10 weeks later, when mAb had cleared from the circulation, MC received DLI that included CD8+ T cells from 2C transgenic mice that bear TCR specific for recipient class I MHC Ld. Using a clonotypic marker to monitor the response, we observed expansion of 2C CD8+ cells, peaking in the spleen on day 7 and then rapidly declining such that 2C CD8+ T cells were <0.1% of splenocytes by day 60. The decline in GVH-reactive T cells was associated with marked apoptosis and a sustained reduction in the expression of IL-7Rα. By day 60, no CTL activity against host cells was detectable. We reasoned that strategies that augment the survival of GVH TE/M might enhance the durability of the GVL response and, in the absence of tissue inflammation induced by conditioning, might not lead to GVHD. Co-stimulation through the tumor necrosis family receptor, OX40, which is expressed on activated T cells, is anti-apoptotic and enhances recruitment of TE/M to the memory pool. Following DLI, OX40 expression on 2C CD8+ T cells peaked on day 7 with somewhat earlier and sustained expression on DLI-derived CD4+ T cells. Since OX40 expression was specific for GVH-reactive T cells, we examined the effect of giving agonistic anti-OX40 antibody on day +5 following DLI. This was associated with rapid and complete conversion to full donor chimerism by day +14, whereas DLI + control antibody recipients had only partially converted by day +28. By day 60 post-DLI, anti-host CTL activity was clearly detectable in anti-OX40 recipients but not in controls. No clinical evidence of GVHD was observed, although histological examination revealed transient mild lymphocytic infiltration of the lamina propria on day +13, which resolved completely by day +18. In further experiments, anti-OX40 administration was associated with marked increases in the numbers of 2C CD8+ T cells in spleen, lymph node and bone marrow following DLI. Furthermore, effector differentiation, as assayed by intracellular expression of interferon-γ by 2C CD8+ T cells, was increased in recipients of anti-OX40 antibody. Of note, we observed a complete inhibition IL-7Rα down-regulation that is normally observed on activated CD8+ T cells following DLI. We conclude that OX40 co-stimulation following delayed DLI to established MC represents a potential means to enhance the magnitude and duration of a GVH reaction without the induction of significant GVHD.

Allogeneic bone marrow cells that facilitate complete chimerism and eliminate tumor cells express both CD8 and T-cell antigen receptor–αβ

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3458-3465 ◽  
Author(s):  
Fengshuo Lan ◽  
Defu Zeng ◽  
Philip Huie ◽  
John P. Higgins ◽  
Samuel Strober
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Bone Marrow Cells ◽  
Antigen Receptor ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Nonmyeloablative host conditioning regimens have been used in clinical allogeneic bone marrow and hematopoietic progenitor transplantation to effectively treat lymphohematopoietic tumors and reduce early toxicity. However, severe graft-versus-host disease (GVHD) remains a major problem. The goal of the current study was to determine whether specific subsets of cells in allogeneic bone marrow transplants can effectively treat the BCL1 B-cell lymphoma in nonmyeloablated BALB/c mouse hosts given a single dose of sublethal (450 cGy) total body irradiation, without inducing severe GVHD. The experimental results show that high doses of whole bone marrow cells from major histocompatiblity complex (MHC)-mismatched donors eliminate both normal and malignant host-type lymphohematopoietic cells without causing injury to nonlymphohematopoietic host tissues. The CD8+T-cell antigen receptor–αβ+(TCRαβ+) T cells within the marrow transplants mediated the killing of the tumor cells via both perforin- and FasL-dependent pathways. Cells present in marrow transplants from either CD8−/− or TCRα−/− donors failed to eliminate malignant and normal host lymphohematopoietic cells. Addition of small numbers of blood mononuclear cells to the marrow inoculum caused lethal GVHD. Thus, the resident allogeneic bone marrow CD8+ TCRαβ+ T cells had the unique capacity to eliminate the host lymphohematopoietic cells without nonlymphohematopoietic tissue injury.

scholarly journals Gamma interferon and lymphotoxin, released by activated T cells, synergize to inhibit granulocyte/monocyte colony formation.

1986 ◽  
Vol 164 (1) ◽  
pp. 263-279 ◽  
Author(s):  
M Murphy ◽  
R Loudon ◽  
M Kobayashi ◽  
G Trinchieri
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Colony Formation ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Inhibiting Activity ◽  
Activated T Cells ◽  
Ifn Gamma ◽  
Simultaneous Production ◽  
Colony Forming Unit

We have shown that lymphocytes stimulated by PHA produce colony-forming unit of granulocyte/monocyte (CFU-GM)-stimulating and -inhibiting activities, IFN-gamma, and lymphotoxin (LT). IFN-gamma is necessary for inhibition of CFU-GM by PHA-conditioned medium (CM), as shown by experiments in which removal of IFN-gamma from PHA-CM abrogated inhibition. However, experiments in which rIFN-gamma was added to IFN-gamma-depleted PHA-CM revealed the presence, in PHA-CM, of other factors that act in synergy with IFN-gamma to inhibit CFU-GM. Fractionation of PHA-CM on a Sephadex G-100 column was used to separate IFN-gamma and LT. Colony-inhibiting activity was eluted in fractions that contained both IFN-gamma and LT activities, identifying LT as a factor present in PHA-CM that synergizes with IFN-gamma to inhibit CFU-GM. Treatment of PHA-CM with mAb against either IFN-gamma or LT completely abrogated the colony-inhibiting activity, demonstrating a requirement for both lymphokines in PHA-CM-induced inhibition of CFU-GM. Experiments using rIFN-gamma and preparations of purified LT confirmed that neither lymphokine alone, when added to bone marrow cells at the concentrations present in PHA-CM, strongly inhibited day 7 or day 14 CFU-GM, but that the two lymphokines, added together, behaved synergistically to inhibit CFU-GM by up to 70%. The inhibition observed using purified preparations of lymphokines shows that synergy between IFN-gamma and LT is sufficient to explain PHA-CM-induced inhibition of CFU-GM. Our findings suggest that activated T cells regulate hematopoiesis through the release of inhibitory as well as stimulatory factors, and that the simultaneous production of IFN-gamma and LT may represent a mechanism of suppression of hematopoiesis in the cases of bone marrow failure associated with the presence of activated T cells.

scholarly journals Induction of Therapeutic Protection in an HPV16-Associated Mouse Tumor Model Through Targeting the Human Papillomavirus-16 E5 Protein to Dendritic Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Oscar Badillo-Godinez ◽  
Adolfo Pedroza-Saavedra ◽  
Veronica Valverde-Garduño ◽  
Victor Bermudez-Morales ◽  
Minerva Maldonado-Gama ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Specific Antigen ◽  
Tumor Model ◽  
Immune Checkpoint Blockade ◽  
Premalignant Lesions ◽  
Mouse Tumor ◽  
Human Papillomavirus 16

HPV E5 is an oncoprotein mainly expressed in premalignant lesions, which makes it an important target for a vaccine to prevent or cure cervical cancer (CC). In this study, we evaluated whether E5 targeted to DEC-205, present in dendritic cells (DCs), could induce a therapeutic protection against HPV16-induced tumor cells in a mouse model. The HPV-16 E5 (16E5) protein was cross-linked to a monoclonal antibody (mAb) specific to mouse DEC-205 (anti-DEC-205:16E5) or to an isotype control mAb (isotype:16E5). Rotavirus VP6 was cross-linked to the mouse anti-DEC-205 mAb (anti-DEC-205:VP6) as a non-specific antigen control. BALB/c mice were inoculated subcutaneously (s.c.) with the 16E5-expressing BMK-16/myc tumor cells, and 7 and 14 days later the mice were immunized s.c. with the conjugates, free 16E5 or PBS in the presence of adjuvant. Tumor growth was monitored to evaluate protection. A strong protective immune response against the tumor cells was induced when the mice were inoculated with the anti-DEC-205:16E5 conjugate, since 70% of the mice controlled the tumor growth and survived, whereas the remaining 30% developed tumors and died by day 72. In contrast, 100% of the mice in the control groups died by day 30. The anti-DEC-205:16E5 conjugate was found to induce 16E5-specific memory T cells, with a Th1/Th17 profile. Both CD4+ and CD8+ T cells contributed to the observed protection. Finally, treating mice that had developed tumors with an anti-PD-1 mAb, delayed the tumor growth for more than 20 days. These results show that targeting 16E5 to DEC-205, alone or combined with an immune checkpoint blockade, could be a promising protocol for the treatment of the early stages of HPV-associated cancer.

Dendritic cells derived from HOXB4-immortalized hematopoietic bone marrow cells

2011 ◽  
Vol 236 (11) ◽  
pp. 1291-1297 ◽  
Author(s):  
Abdul Mannan Baru ◽  
Jayendra Kumar Krishnaswamy ◽  
Anchana Rathinasamy ◽  
Michaela Scherr ◽  
Matthias Eder ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Surface Expression ◽  
Hematopoietic Stem ◽  
Hematopoietic Bone Marrow

Dendritic cells (DCs) are essential for the generation and modulation of cell-mediated adaptive immunity against infections. DC-based vaccination involves transplantation of ex vivo-generated DCs loaded with antigen in vitro, but remains limited by the number of autologous or allogeneic cells. While in vitro expansion and differentiation of hematopoietic stem cells (HSCs) into DCs seems to be the most viable alternative to overcome this problem, the complexity of HSC expansion in vitro has posed significant limitations for clinical application. We immortalized lineage-depleted murine hematopoietic bone marrow (lin−BM) cells with HOXB4, and differentiated them into CD11c+MHCII+ DCs. These cells showed the typical DC phenotype and upregulated surface expression of co-stimulatory molecules on stimulation with various toll-like receptor ligands. These DCs efficiently presented exogenous antigen to T-cells via major histocompatibility complex (MHC) I and II and viral antigen on infection. Finally, they showed migratory capacity and were able to generate antigen-specific primed T-cells in vivo. In summary, we provide evidence that HOXB4-transduced lin−BM cells can serve as a viable means of generating fully functional DCs for scientific and therapeutic applications.

scholarly journals Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies against Cancer

Antibodies ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 25
Author(s):  
Violet Y. Tu ◽  
Asma Ayari ◽  
Roddy S. O’Connor
Keyword(s):  
T Cells ◽  
Lactic Acid ◽  
T Cell ◽  
Tumor Cells ◽  
Cell Biology ◽  
Redox Balance ◽  
Hematologic Malignancies ◽  
Activated T Cells ◽  
Unique Challenge ◽  
Cell Therapies

T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T cells. Local metabolism is an important consideration for activated T cells as they undergo bursts of migration, proliferation and differentiation in hostile soil. Tumor cells and activated T cells both produce lactic acid at high rates. The role of lactic acid in T cell biology is complex, as lactate is an often-neglected carbon source that can fuel TCA anaplerosis. Circulating lactate is also an important means to regulate redox balance. In hypoxic tumors, lactate is immune-suppressive. Here, we discuss how intrinsic- (T cells) as well as extrinsic (tumor cells and micro-environmental)-derived metabolic factors, including lactate, suppress the ability of antigen-specific T cells to eradicate tumors. Finally, we introduce recent discoveries that target the TME in order to potentiate T cell-based therapies against cancer.

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