scholarly journals Polysaccharides from Chinese Herbal Lycium barbarum Induced Systemic and Local Immune Responses in H22 Tumor-Bearing Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Xiangliang Deng ◽  
Shuang Luo ◽  
Xia Luo ◽  
Minghua Hu ◽  
Fangli Ma ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Tumor Growth ◽  
Tumor Tissue ◽  
The Body ◽  
Lycium Barbarum ◽  
Functional Changes ◽  
Chinese Herbal ◽  
Tumor Bearing

Lycium barbarum polysaccharide (LBP) is isolated from the fruit of Chinese herbal Lycium barbarum. Previous studies had demonstrated that LBP could inhibit tumor growth and enhance the immunity in mice. However, the effect of LBP on systemic and local immune responses in vivo, especially on phenotypic and functional changes of T cells, is still largely unknown. In the present study, we investigated the effects of LBP on systemic and local T cell-dependent antitumor immune responses in H22 tumor-bearing mice. The results showed that LBP could inhibit the solid tumor growth in mice, but showed little effect on the body weight or spleen index. Furthermore, LBP could maintain high levels of T cells in peripheral blood (PB), tumor draining lymph node (TDLN), and tumor tissue, prevent the increase of Tregs while promote infiltration of CD8+ T cells in tumor tissue, inhibit the production of TGF-β1 and IL-10 in serum, decrease the exhaustion phenotype of T cells, and maintain cytotoxicity of lymphocytes. Taken together, our results demonstrated that LBP simultaneously induced systemic and local immune responses in H22 tumor-bearing mice by alleviating immunosuppression and maintaining antitumor immune responses in mice.

In Vivo Visualization of Stat3 Activation in Myeloid Cells during Inflammation and Tumor Growth.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3434-3434
Author(s):  
Pedro Horna ◽  
Fengdong Cheng ◽  
Richard Jove ◽  
Linda Mora ◽  
Eduardo M. Sotomayor
Keyword(s):  
Steady State ◽  
Immune Responses ◽  
Tumor Growth ◽  
Peripheral Blood ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Tumor Bearing ◽  
Inflammatory Site ◽  
Number Of Cells

Abstract Signal transducer and activator of transcription 3 (Stat3) is a key mediator of several cytokine and growth factor signaling pathways. On myeloid cells, activation of Stat3 to its phosphorylated form (pStat3) has been shown to negatively regulate inflammatory responses and play a central role in the decision leading to immune activation versus immune tolerance of antigen-specific T-cells1. Little is still known however, about the status of Stat3 signaling in myeloid cells in the steady state and during ongoing immune responses in vivo. To address this question we recently developed flow-cytometric and immuno-histochemistry assays that have allowed us to visualize the in vivo dynamics of Stat3 activation in myeloid cells during immune responses leading to divergent outcomes: productive inflammatory response to adjuvant immunization and tumor-induced unresponsiveness or tolerance. In the steady state we found that in peripheral blood only Ly6G+ polymorphonuclear cells display a positive nuclear staining for pStat3. Analysis of lymphoid organs revealed that although Stat3 protein was expressed almost ubiquitously on spleen sections of normal mice, only a small number of cells were positive for pStat3. Following immunization with complete Freund adjuvant (CFA) a dramatic increase in the number of cells expressing pStat3 was observed in the peripheral blood and spleen of treated animals. Ly6G+ pStat3+ were rapidly recruited from the blood to the inflammatory site where they now displayed significantly decreased levels of pStat3. During the growth of a subcutaneous tumor, a similar increase in the number of cells expressing pStat3 was observed in the blood and spleen of tumor-bearing mice. Further analysis by flow cytometry revealed that pStat3 expression was restricted to two sub-populations: a) CD11b+ myeloid cells expressing the lineage marker Gr-1 and b) Ly6G− mononuclear cells unable to down-regulate Stat3 activity following their migration from the blood into peripheral tissues. In vivo depletion of Gr-1+ cells eliminated most of the pStat3+ cells in tumor bearing mice. The immunoregulatory properties of these Gr-1+ cells was highlighted by the demonstration that in their absence, in vivo immunization with a peptide derived from influenza hemagglutinin (HA) in CFA markedly enhanced the priming of anti-HA specific CD4+ T-cells. More importantly, in animals depleted of Gr-1+ cells, the outcome in response to a tolerogenic stimuli was T-cell activation rather than tolerance induction. Taken together, although similar changes in the number of cells expressing pStat3 was observed in response to adjuvant immunization and during tumor progression, an important difference might relate to the extent of Stat3 activation in myeloid cells following their migration to the site of stimuli. While down-regulation of Stat3 in myeloid cells at the inflammatory site is an early event during productive inflammatory responses, a sustained Stat3 activation in myeloid cells such as that observed during tumor growth may provide an explanation for the state of immune unresponsiveness associated with malignancies.

The Role of Pretransplant Conditioning On Graft-Versus-Leukemia Effects: Migration Matters.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3563-3563
Author(s):  
Ji-Young Lim ◽  
Mi-Sun Choi ◽  
Eun Young Choi ◽  
Hyewon Youn ◽  
Chang-Ki Min
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Cd4 T Cells ◽  
Tumor Tissue ◽  
Cell Trafficking ◽  
Tnf Α ◽  
Ifn Γ ◽  
Conditioning Intensity

Abstract Abstract 3563 Poster Board III-500 The therapeutic potential of allogeneic hematopoietic stem cell transplantation (HSCT) relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells by immunologic mechanisms. However, the relationship of conditioning intensity to GVL effect has not been clearly established independent of immunosuppression or the tolerance induced by mixed donor-host chimerism. Using a murine allogeneic HSCT model, we have compared two total body irradiation (TBI) doses (1,300 vs. 900 cGy), both of which provided complete donor engraftment and elimination of host lympho-hematopoetic cells. We used C57BL/6 (H-2b) → B6D2F1 (H-2b/d) model of GVHD, which differ at major and minor histocompatibility loci, to address the role of conditioning intensity on the GVL effect. Lethally irradiated (either 900 or 1300 cGy) recipient mice were transplanted with either C57BL/6 (allogeneic) or B6D2F1 (syngeneic) bone marrow (5 × 106) and spleen T cells (1 × 106) on day 0 and then P815 (H-2d) mastocytoma cells (1 × 106) injected subcutaneously on day 1 to generate a GVL model. As expected, GVHD morbidity after the higher TBI dose was aggravated compared to the lower TBI dose (P<.05). Among the syngeneic recipients, the injection of P815 cells into the recipient skin led to progressive tumor growth and death of about 100% 21 days after transplant regardless of the TBI dose. In contrast, tumor growth was remarkably suppressed and tumor death was not observed in the allogeneic recipients. Surprisingly, tumors in the allogeneic recipients receiving 1300 cGy TBI exhibited markedly delayed growth in vivo compared to those with 900 cGy (tumor volume on day 42, 428 vs. 8735mm3, P<.01), which was associated with an increase in the in vivo cytotoxicity using comparing the clearance of infused allogeneic B cells labeled with CFSE reflecting the enhanced alloimmune reactivity. To ask whether the diminished GVL effect after the lower TBI dose was due to reduced production of inflammatory cytokines, we measured the levels of TNF-α or IFN-γ in recipient sera on days 6, 28 and 42 after transplantation and did not find any significant difference according to the intensity of radiation dose (P>.05). In parallel, the in vitro P815-specific TNF-α or IFN-γ responses of splenocytes were comparable between the two doses. The percentages of donor T cells to undergo proliferation or apoptosis in response to alloantigens in vivo between the two TBI doses also were comparable (P>.05). Collectively, these data indicate that the impaired ability of alloreacive T cells to inhibit tumor growth after the lower TBI dose was not attributed to an intrinsic defect in T-cell expansion and activation. We next analyzed the spleen for the number of donor CD4+ and CD8+ T cells and observed no difference between the two TBI doses. In contrast to spleen, the number of CD8+ but not CD4+ T cells from the recipients that had received 1300 cGy was significantly increased in the skin (P<05). The effector function of donor CD8+ and CD4+ cells in both spleen and tumor tissue was examined by intracellular staining for IFN-γ. In the spleen, the percentages of CD8+ and CD4+ T cells expressing IFN-γ were not different between the two TBI doses. (5.9% vs 4.8%, P>.05, and 7.6% vs. 6.5%, P>.05 respectively) By contrast, 45.5% and 50.3% of CD8+ and CD4+ T cells, respectively, isolated from the tumor tissue of recipients receiving the higher TBI dose were IFN-γ; secreting cells, whereas only 25.5% and 16.3% of those cells from the tumor tissue of recipients treated with the lower dose showed this phenotype (P<.01 and <.05, respectively). After the higher TBI dose, secondary lymphoid organ homing receptors including CD62L and CCR7 were down-regulated on donor CD8+ T cells while CD44 expression was up-regulated compared to the lower TBI dose, which may facilitate migration to the tumor sites. In summary, the higher TBI dose (1300 vs. 900 cGy) resulted in significantly enhanced GVL effect, and the alterations in effector T cell trafficking into tumor tissue are the most likely mechanism. Moreover, T-cell activation and function were largely comparable between these conditioning regimens. This provides the rationale for targeting T cell trafficking by inflammation, possibly in combination with integrin or chemokine receptor agonists as a new therapeutic approach in leukemia relapse after allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

Dipeptidyl Peptidase Inhibition Accelerates Dendritic Cell Cross Priming of Tumor-Reactive T Cells Resulting in Regression of Established Tumors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2579-2579
Author(s):  
Meghaan Walsh ◽  
Aviva C Krauss ◽  
Jessica PE Davis ◽  
Su Young Kim ◽  
Martin Guimond ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Regression ◽  
High Dose ◽  
Complete Regression ◽  
Tumor Bearing ◽  
Dc Vaccine ◽  
Dipeptidyl Peptidases

Abstract BACKGROUND: PT-100 is an aminoboronic dipeptide that competitively inhibits dipeptidyl peptidases. While PT-100 has no direct effect on tumor cells in vitro, it exhibits potent antitumor effects in vivo. We have shown that female C57BL/6 (B6) mice with MB49 tumors, which naturally express the male minor histocompatibility antigen complex (HY), are primed to HY, but the immune response is insufficient to control tumor growth. In this study, we used the well-characterized HY antigen system to examine the immunomodulatory effects of PT-100 during treatment-induced tumor regression. METHODS: B6 female mice were inoculated subcutaneously with MB49 (106 cells) on day 0 and treated daily with PT-100 by gavage. For re-challenge experiments mice received high dose MB49 (3×106 cells) three weeks after complete regression of primary tumors. IFN-g ELISPOT was used to measure HY antigen specific T cell responses in the spleen and lymph nodes (LNs) during tumor growth. For adoptive transfer experiments, T cells were magnetic-bead purified from LNs and spleens of tumor-bearing PT-100 treated, tumor-bearing sham treated, or naïve mice and injected intravenously into Rag1−/− recipients (1.2×106 cells) which were then inoculated with high dose MB49. T cells were depleted with monoclonal antibodies to CD4 and CD8. Dendritic cells (DCs) were depleted with diphtheria toxin (DT) in bone marrow chimeras expressing the DT receptor under the CD11c promoter. DC activation examined by flow cytometry. For vaccine experiments, HY-expressing DCs were cultured from male B6 bone marrow and injected intraperitoneally (1×105 cells). RESULTS: PT-100 treatment resulted in complete regression of MB49, even when limited to the first week (days 3–7) during tumor progression. Treatment started later than week 1 was insufficient to establish consistent, complete tumor regression. High-dose re-challenge of PT-100 treated mice resulted in initial growth followed by regression without additional PT-100. IFN-gELISPOT revealed a robust response against HY in spleens of controls on day 17. Interestingly, PT-100 treated mice had quantitatively similar priming, but the response peaked earlier (day 10), just prior to tumor regression. Purified T cells from PT-100 treated donors collected on day 17 mediated markedly enhanced tumor protection compared to recipients of T cells from sham treated tumor-bearing mice despite significantly more HY-reactive cells in the spleen and LNs of sham treated-tumor bearing mice by that time. T cell or DC depletion independently abrogated the anti-tumor effect of PT-100 and treatment with PT-100 increased CD80 and CD86 expression on LN DC populations in vivo. Although HY DC vaccination does not affect tumor growth, supplementation of the DC vaccine with PT-100 mediated a therapeutic effect resulting in regression of well-established tumors. CONCLUSIONS: PT-100 establishes a consistent and potent antitumor effect against MB49 dependent on T cells and DCs. Treatment results in a memory response that is protective against high dose MB49 re-challenge. PT-100-induced tumor regression is associated with enhanced early tumor priming, associated with increases in activated DCs. T cells from PT-100 treated mice elicit superior protection upon adoptive transfer compared to shams, despite quantitatively less tumor-primed T cells, suggesting the PT-100 antitumor effect may involve a qualitative difference in T cell function. PT-100 given as an adjuvant to a DC vaccine results in increased potency and regression of established tumors. Inhibition of dipeptidyl peptidases modulate naturally occurring anti-tumor immune responses and contribute to the generation of a therapeutic anti-cancer vaccine.

scholarly journals 857 Selective Treg depletion in solid tumors with ALD2510, a novel humanized CD25-specific, IL-2 sparing monoclonal antibody

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A898-A898
Author(s):  
Jemila Houacine ◽  
Anne Marie-Cardine ◽  
Aude Le Roy ◽  
Jérôme Giustiniani ◽  
Riad Abes ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Tumor Growth ◽  
Single Agent ◽  
Interleukin 2 ◽  
T Cell Subsets ◽  
Treg Depletion ◽  
Cd25 Expression ◽  
Tumor Biopsies

BackgroundRegulatory T cells (Tregs) inhibit immune responses in solid cancers using cell-cell contacts and anti-inflammatory cytokine release. Also, due to high and constitutive levels of IL2Ralpha chain (CD25) expression, Tumor infiltrating (TIL)-Tregs cells preferably consume local Interleukin-2 (IL2), thus depriving conventional T cells from IL2-induced activation and proliferation. Therefore, the selective depletion of TIL-Tregs using therapeutic antibodies targeting CD25 represents a promising strategy to unleash tumor-specific immune responses in solid cancers.MethodsCD25 expression was evaluated by flow and mass cytometry on T -cell subsets from tumor biopsies collected in patients with various solid cancers (Breast, Endometrial and Cervix). ALD2510 potency was demonstrated in vitro and in vivo in human CD25 Knock-In huGEMM (huCD25-KI) MC38-bearing mice and in CD34+ humanized NSG mice grafted with human cancer cell lines (MDA-MB-231 and HT29).ResultsIn tumor biopsies, CD25 is highly and homogeneously expressed by TIL-Tregs, while being much less expressed by only a fraction of conventional CD4+ T cells and barely expressed by TIL-CD8+ cells. This confirms CD25 as the most selective marker to target TIL-Tregs in cancer patients.In vitro, ALD2510 shows potent ADCC and ADCP as well as strong Treg depletion capacity. Importantly, CD8+ and CD4+ conventional T cells are not impacted by ALD2510 even after activation confirming ALD2510 ability to selectively deplete Tregs. Accordingly, ALD2510 neither blocks IL-2 binding to CD25 nor inhibits IL-2 induced proliferation of activated T cells. In CD34+-humanized mice, ALD2510 efficiently depletes human Tregs but spares conventional T cells. Also, in the MC38 model in huCD25-KI mice, ALD2510 shows a strong anti-tumor activity as a single agent with 60% overall tumor growth inhibition together with massive Treg depletion 7 days after a single administration. In addition, combination of ALD2510 with anti-PD1 leads to complete tumor regression and strong activation of conventional T cells. Importantly, Basiliximab, a CD25-specific IL-2 blocking antibody, although efficient at depleting Treg cells, did not impact tumor growth, thus demonstrating that the IL-2 sparing feature of ALD2510 is critical to elicit anti-tumour response in vivo.ConclusionsThis preclinical data package supports CD25 as a potent and selective Treg marker allowing Tregs depletion while sparing conventional T cells. In this context, ALD2510, a novel humanized CD25-specific and IL-2 sparing antibody presents all the required attributes for selective and efficient TIL-Tregs depletion, making it a promising drug candidate to treat a broad range of solid tumor patients.Ethics ApprovalThe studies involving human material were approved by the ethical committee “Comité de Protection des Personnes Sud Méditerranée » under approval numbers 1362 and 1048. All participants gave informed consent before taking part.

scholarly journals 753 InhibigenTM administration promotes aberrant T cell responses in cancer but may be beneficial for amelioration of autoimmune disease

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A787-A787
Author(s):  
Victoria DeVault ◽  
Hanna Starobinets ◽  
Julie Arnold ◽  
Stephanie Rinaldi ◽  
Charley Hubbard ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
T Cell Responses ◽  
Cell Responses ◽  
Tumor Bearing ◽  
Melanoma Model ◽  
Cancer Immunotherapies

BackgroundSelecting neoantigens that generate robust anti-tumor T cell responses remains a challenge for cancer immunotherapy design. The ATLASTM platform, a functional recall assay using patient autologous cells, identifies both stimulatory and inhibitory (Inhibigen) neoantigens via up- or downregulation of T cell cytokine secretion.1 We propose that stimulatory neoantigens are ideal targets for cancer vaccines and T cell therapies. In contrast, data suggest that Inhibigens be excluded, due to their association with accelerated tumor growth and dampened immunity in a murine melanoma model.2 While detrimental to cancer immunotherapy, the Inhibigen-associated downregulation of cytokine production may be beneficial in the context of autoimmunity.MethodsATLAS screens were performed as previously described.1 2 Peptide vaccines containing tumor-specific neoantigens ± Inhibigens were evaluated in prophylactic and therapeutic B16F10 melanoma tumor models for immunogenicity and efficacy. RNAseq analysis was performed on T cells sorted from draining lymph nodes of vaccinated tumor-bearing mice. For experimental autoimmune encephalomyelitis (EAE) studies, mice were administered a vaccine containing MOG peptide ± the melanoma MMP9FS Inhibigen. Immune responses and phenotypic analyses for both models were measured by flow cytometry, ELISPOT, and immunohistochemistry.ResultsIn the melanoma model, inclusion of the Inhibigen MMP9FS accelerated tumor growth in a non-dose dependent manner and abrogated immune responses. RNAseq of T cells from tumor-bearing mice vaccinated with MMP9FS showed a higher level of differentially expressed genes (adjusted P value of <0.05) in TCR-signaling regulation and suppressor GO pathways (>5 distinct pathways/gene) as compared to stimulatory controls, indicating Inhibigen-specific effects on T cells. In the EAE model of autoimmunity, animals treated with MOG peptide + MMP9FS exhibited dampened anti-MOG immune responses, delayed disease onset, reduced disease incidence and scoring (average 1 vs. 3) and decreased spinal cord immune infiltration as compared to control vaccination. These data indicate that Inhibigen administration has the potential to ameliorate autoimmune sequelae, independent of cognate antigen expression.ConclusionsFunctional identification and exclusion of Inhibigens from cancer immunotherapies may be critical to protective immunity since their inclusion can result in quelling of otherwise beneficial immune responses. Conversely, Inhibigen-specific responses can dampen destructive autoimmune sequelae. Mechanistic studies show altered T cell signaling pathways in the context of therapeutic Inhibigen vaccination. These data suggest that Inhibigen-specific responses, while detrimental for the treatment of cancer, may have a therapeutic benefit in other disease contexts.ReferencesNogueira C, Kaufmann JK, Lam H, Flechtner JB. Improving cancer immunotherapies through empirical neoantigen selection. Trends in Cancer 2018;4(2):97–100.Lam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021;11(3):696–713.Ethics ApprovalAll animal studies were undertaken in conformity with the Cambridge, MA Ordinance 1086 of the city's Municipal Code and in accordance with the policies and protocols approved by Genocea's Institutional Animal Care and Use Committee (IACUC).

scholarly journals Curcumin Administered in Combination with Glu-GNPs Induces Radiosensitivity in Transplanted Tumor MDA-MB-231-luc Cells in Nude Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Mengjie Li ◽  
Ling Lin ◽  
Tingting Guo ◽  
Yujian Wu ◽  
Jiayi Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Nude Mice ◽  
Tumor Tissue ◽  
The Body ◽  
Model Group ◽  
Bioluminescence Intensity ◽  
X Ray ◽  
Transplanted Tumor ◽  
Tumor Bearing

Curcumin is a type of plant polyphenol extracted from Curcuma longa L. rhizome, which demonstrates antitumor activity in breast cancer cells in vitro. To investigate the combined effect and possible mechanism of curcumin and glucose-gold nanoparticles (Glu-GNPs), the radiosensitivity of breast carcinoma xenografts was assessed in nude mice. MDA-MB-231 cells labeled with firefly luciferase were inoculated into the mammary fatty pads of nude mice to establish a transplantation tumor model of human breast cancer. The tumor-bearing mice were treated with different drugs (curcumin, Glu-GNPs, and cisplatin) for 3 weeks prior to radiotherapy. The body weights and tumor volumes of the mice were measured in regular intervals. Tumor bioluminescence intensity was determined in real-time using an in vivo bioluminescence imaging system to monitor tumor growth. Transplanted tumor tissue samples were taken for hematoxylin and eosin (HE) staining, and the expression of VEGF, HSP90, HIF-1α, and MMP9 was evaluated via reverse transcription-quantitative PCR or immunohistochemistry. The results revealed that the breast tumor-bearing nude mouse model was successfully established, as evidenced by a stable expression of luciferase. Curcumin inhibited the growth of tumors without causing significant weight loss in mice. Furthermore, additive inhibition was demonstrated when curcumin was administered in combination with Glu-GNPs and irradiation. Tumor bioluminescence intensity was decreased in the model group following curcumin, Glu-GNPs, and irradiation treatment. HE staining demonstrated that transplanted tumors were malignant, with necrotic tissue exhibited centrally. It was concluded that curcumin administered in combination with Glu-GNPs and X-ray irradiation could reduce the protein expression of VEGF, HSP90, HIF-1α, and MMP9 in tumor tissue when compared with the model group. Curcumin and Glu-GNPs administered with X-ray irradiation significantly inhibited tumor growth and induced radiosensitivity, which may be associated with the inhibition of angiogenesis in tumor tissue.

C5a Complement Depletion Suppresses In Vivo B Lymphoma Progression and Enhances Development Of Cellular Anti-Tumor Immune Response

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1837-1837
Author(s):  
Suresh Veeramani ◽  
George J. Weiner
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cd8 T Cells ◽  
B Lymphoma

Abstract Background Proteins within the complement system have complex effects on cellular immune responses. In previous studies, we found that active complement components, especially C5a, can dampen the development of antigen-specific immune responses following vaccination with a model antigen, in part by promoting generation of APC-induced T regulatory (Treg) cells. These studies also demonstrated that B lymphoma cell lines exposed to complement can induce Treg generation in vitro. The current study was designed to address whether depletion of C5a could enhance development of a cellular anti-lymphoma immune response in vivo. Methods Immunocompetent Balb/C mice were inoculated subcutaneously with syngeneic A20 B lymphoma cells mixed with either 10 μg of rat anti-mouse C5a monoclonal antibody (mAb) or 10 μg of isotype-matched Rat IgG2a control mAb. Tumor growth was followed. In select experiments, mice were sacrificed and analyzed for the percentage and activity of tumor-infiltrating T cells and A20-specific splenic T cell responses. Results 1. Tumor progression. Lymphoma grew more slowly in mice treated with anti-C5a mAb compared to mice treated with control mAb (p<0.05) {Fig. 1). 2. Intratumoral T cells. Tumors from mice treated with anti-C5a mAb had higher CD8+ T cell infiltration compared to mice treated with control mAb (p=0.002) (Fig. 2). Tumor-infiltrating CD8+ T cells showed a trend towards higher intracellular IFNg production in mice treated with anti-C5a mAb compared to control mAb (p=0.051). 3. Splenic T cells. Splenic T cells from mice treated with anti-C5a mAb produced IFNg to a greater degree than did splenic T cells from control mice when splenocytes were cultured with irradiated A20 cells in vitro (p=0.041) (Fig. 3). There was a trend towards decreased numbers of splenic CD4+CD25highFoxp3+ Tregs in C5a-depleted mice compared to control mice. Conclusions Depletion of C5a at the site of tumor inoculation slows tumor growth and increases the number of tumor infiltrating CD8 T cells in a syngenic immunocompetent model of lymphoma. A trend towards enhanced production of IFNg in the tumor infiltrating T cells, increased numbers of tumor-specific splenic T cells, and reduced numbers of splenic Tregs, suggests intratumoral C5a depletion can enhance tumor-specific immune responses both within the tumor and systemically. Ongoing studies are exploring the molecular mechanisms involved in C5a-promoted tumor progression and the use of C5a depletion as a novel strategy to improve anti-tumor immunity. Disclosures: No relevant conflicts of interest to declare.

scholarly journals EXTH-42. QUANTITATIVE BIODISTRIBUTION OF ADOPTIVELY TRANSFERRED T CELLS IN BRAIN TUMOR-BEARING MICE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi91-vi91
Author(s):  
Lan Hoang-Minh ◽  
Fernanda Pohl-Guimarães ◽  
Angelie Rivera-Rodriguez ◽  
Seth Currlin ◽  
Kevin Otto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
The Body ◽  
Confocal Imaging ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
Light Sheet Microscopy ◽  
Tumor Bearing ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment strategy against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including those with lesions within the central nervous system. Importantly, immunologic surrogate endpoints that correlate with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of exogenously administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS T cells were isolated from the spleens of DsRed transgenic C57BL/6 mice and injected intravenously, after in vitro expansion and activation, in murine KR158B glioma-bearing mice. To determine transferred T cell spatial distribution, brains, lymph nodes, hearts, lungs, spleens, livers, kidneys and stomachs were isolated for active clearing, immunostaining, and 3D imaging using light sheet microscopy, or processed for fluorescent immunohistochemistry and confocal imaging. Transferred T cell quantification in various organs was performed using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle labeling. T cell distribution was also assessed in vivo using IVIS and MPI. RESULTS The spleen, liver, and lungs accounted for more than 90% of transferred T cells in the body. The proportion of DsRed T cells in tumor-bearing brains was found to be very low, hovering below 1% (and representing ~15% of total tumor-infiltrating lymphocytes). Transferred T cells mostly concentrated at the periphery of the tumor mass and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors likely requires optimization of delivery route, dosing regimen, and modification of tumor-specific lymphocyte trafficking and effector functions in order to achieve maximal penetration and persistence at sites of invasive tumor growth.

scholarly journals Effects Induced In Vivo by Exposure to Magnetic Signals Derived From a Healing Technique

Dose-Response ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 155932582090774
Author(s):  
Sarah Beseme ◽  
Loren Fast ◽  
William Bengston ◽  
Michael Turner ◽  
Dean Radin ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Malignant Tumors ◽  
Biological Response ◽  
Daily Basis ◽  
The Body ◽  
Control Group ◽  
Blood Levels ◽  
Therapeutic Success ◽  
Tumor Bearing

Energy healing is a therapy said to manipulate and balance the flow of “energies” in the body. One such technique, the Bengston Healing Method (BHM), has shown some success in healing malignant tumors in animals and humans, but the mechanism of action and factors influencing therapeutic success of this method are poorly understood. In this study, we tested in vivo the antitumor potential of magnetic signals recorded during BHM healing. Balb/c mice engrafted with 4T1 breast cancer cells were exposed to this recording for 4 h/d on a weekly or daily basis for 28 days; control mice were not exposed at all. Tumors showed a trend to grow slower in the treatment versus control group during the fourth week of treatment. Elevated leukocyte counts, associated with an increase in blood levels of granulocyte–macrophage colony stimulating factor and interleukin-6, were observed in tumor-bearing mice exposed to the BHM recording but not in healthy animals exposed to the recording. This suggests that exposure to a recording of BHM may induce a biological response in tumor-bearing mice, but limited effects on tumor growth when observed within the predefined end point of 28 days. Studies involving longer end points are recommended to observe the progression of tumor growth.

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