scholarly journals Metabolomic profiling of tumor-infiltrating macrophages during tumor growth

2020 ◽  
Vol 69 (11) ◽  
pp. 2357-2369
Author(s):  
Naoki Umemura ◽  
Masahiro Sugimoto ◽  
Yusuke Kitoh ◽  
Masanao Saio ◽  
Hiroshi Sakagami
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Early Stage ◽  
Suppressor Cells ◽  
Tca Cycle ◽  
Tumor Stage ◽  
Cell Number ◽  
Tumor Bearing ◽  
Intracellular Metabolism

Abstract Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are both key immunosuppressive cells that contribute to tumor growth. Metabolism and immunity of tumors depend on the tumor microenvironment (TME). However, the intracellular metabolism of MDSCs and TAMs during tumor growth remains unclear. Here, we characterized CD11b+ cells isolated from a tumor-bearing mouse model to compare intratumoral TAMs and intrasplenic MDSCs. Intratumoral CD11b+ cells and intrasplenic CD11b+ cells were isolated from tumor-bearing mice at early and late stages (14 and 28 days post-cell transplantation, respectively). The cell number of intrasplenic CD11b+ significantly increased with tumor growth. These cells included neutrophils holding segmented leukocytes or monocytes with an oval nucleus and Gr-1hi IL-4Rαhi cells without immunosuppressive function against CD8 T cells. Thus, these cells were classified as MDSC-like cells (MDSC-LCs). Intratumoral CD11b+ cells included macrophages with a round nucleus and were F4/80hi Gr-1lo IL-4Rαhi cells. Early stage intratumoral CD11b+ cells inhibited CD8 T cells via TNFα. Thus, this cell population was classified as TAMs. Metabolomic analyses of intratumoral TAMs and MDSC-LCs during tumor growth were conducted. Metabolic profiles of intratumoral TAMs showed larger changes in various metabolic pathways, e.g., glycolysis, TCA cycle, and glutamic acid pathways, during tumor growth compared with MDSL-LCs. Our findings demonstrated that intratumoral TAMs showed an immunosuppressive capacity from the early tumor stage and underwent intracellular metabolism changes during tumor growth. These results clarify the intracellular metabolism of TAMs during tumor growth and contribute to our understanding of tumor immunity.

scholarly journals The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment

2020 ◽  
Author(s):  
Mohammad H. Rashid ◽  
Thaiz F. Borin ◽  
Roxan Ara ◽  
Raziye Piranlioglu ◽  
Bhagelu R. Achyut ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Cell Types ◽  
Biological Macromolecules

AbstractMyeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.

scholarly journals 600 BR101801 stimulates anti-tumor immunity and enhances the efficacy of radiation in a syngeneic model

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A630-A630
Author(s):  
Seungho Wang ◽  
Yi Na Yoon ◽  
Mi kwon Son ◽  
Soo Jung Kim ◽  
Bo Ram Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Synergistic Effects ◽  
Suppressor Cells ◽  
Tumor Bearing ◽  
The U.S ◽  
Syngeneic Model

BackgroundBR101801 is an inhibitor of PI3K γ/δ and DNA-PK. It has received clinical approval from the U.S. FDA as an anticancer drug candidate, and phase 1a/1b is ongoing in the U.S. and South Korea. According to the prior studies PI3K γ/δ inhibition exhibits anticancer immune effects by changing the tumor microenvironment [1]. In addition, ionizing radiation (IR) activates the immune response by causing the destroyed cells to act as antigens [2]. Therefore, the combination of BR101801 and IR can induce cancer cell death and amplify anticancer immune effects. This study aims to demonstrate efficacy of the BR101801 as a potent cancer immunotherapy.MethodsThe enzymatic potency of PI3K isotype and DNA-PK was analyzed by Eurofins. The effects of BR101801 on cell viability were evaluated in 4T1 (breast cancer) and CT-26 (colon cancer) cells for 72 h using WST-8 assay. For in vivo studies, the tumor (4T1 or CT-26)-bearing syngeneic mice were treated with BR101801. To evaluate the synergistic effect, CT-26 tumor-bearing syngeneic mice were treated with vehicle, BR101801, IR (2 Gy or 7.5 Gy), and BR101801 + IR. Immune cells from the spleen or tumor were quantified by flow cytometry.ResultsIn vitro selectivity and target potency of BR101801 on different PI3K isotypes and DNA-PK were studied in a cell-free system. The biochemical IC50 values of BR101801 for PI3K -γ, -δ, and DNA-PK were 15 nM, 2 nM, and 6 nM, respectively. In vitro 50% of maximal inhibition of cell proliferation (GI50) in 4T1 and CT26 cell lines were both above 10 μM. In 4T1 and CT-26 syngeneic models, BR101801 showed the highest tumor inhibitor efficacy (Figure 1). In particular, regulatory T cells (Tregs) & Myeloid derived suppressor cells (MDSC) were decreased and CD8+ T cells were increased in the spleens isolated from the tumor-bearing mice. Compared with other PI3K inhibitors, BR101801 had the highest efficacy, confirming that it changes the immune microenvironment. Moreover, BR101801 was synergistic in combination with 2 Gy or 7.5 Gy of IR in the syngeneic model. Notably, Tregs & Macrophage2 were decreased and CD8+ T cells were increased in the tumor tissue, confirming that the anticancer efficacy.Abstract 600 Figure 1Synergistic effect with ionizing radiation In VivoThe combination of BR101801 and ionising radiation showed synergistic effects in the CT-26 Syngeneic model. BR101801 increases anti-cancer immune cells, CD8 + T cells, and decreases immune suppressor cells Tregs and macrophages through a combination of radiation, resulting in immuno-cancer effects.ConclusionsBR101801 demonstrated an anticancer immune effect by changing the tumor microenvironment and showed synergistic effects with radiation combination therapy. We will confirm the anticancer immunity effect in ongoing clinical trials.ReferencesOkkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016; 10: 1090–1105.McKelvey K, Hudson A, Back M, Eade T, Diakos C. Radiation, inflammation and the immune response in cancer. Mammalian Genome. 2018;9:843–865Ethics ApprovalThe protocol and any amendment(s) or procedures involving the care and use of animals in this study were reviewed and approved by the Institutional animal Car and Use Committee (IACUC) of BoRyung Pharm. prior to conduct.[Approval number:BR18130]

VIP-Receptor Antagonist Enhanced Antileukemic Activity In Mice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1664-1664
Author(s):  
Jian-Ming Li ◽  
Christopher Thomas Petersen ◽  
Katarzyna Anna Darlak ◽  
Hyun Don Yun ◽  
Bruce R Blazar ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Tumor Bearing ◽  
Tnf Α ◽  
Ifn Γ ◽  
Fas L ◽  
Vip Receptor

Background and Objective We have previously published that antagonizing vasoactive intestinal peptide (VIP) receptors dramatically decreases PD-1 expression on activated CD8+ T-cells and increases antiviral immunity (Blood 2013, 121:2347-51; PLoS One 2013, 8: e63381). Herein we tested whether short-term pharmacological antagonism of VIP signaling could induce anti-tumor immune responses in mice. Methods B6 mice were inoculated with 0.5 - 2 x 106 luciferase+ murine acute myeloid leukemia cells (Luc+ C1498) and B10BR mice were injected with 3 x 106 luciferase+ murine acute T-cell lymphoma cells (Luc+ LBRM) through tail vein. Mice were treated with one or more daily s.c. injections of 10 μg VIPhyb. Survival of groups that received 1, 3 or 7 doses of VIPhyb were compared with PBS treated controls. Tumor growth was monitored weekly by bioluminescence imaging (BLI). Cytokine expression and expression of immune markers PD-1, PD-1H (VISTA), and PD-L1 on blood and spleen leukocytes were analyzed by flow cytometry. Results Long-term survival (day 80) of tumor-bearing B6 and B10BR mice that received a single-dose of VIPhyb one day before tumor inoculation was 80% for both mouse strains harboring both leukemia cells (p<0.01 vs. control, B6 n=10 and B10BR n=5, Figure 1). A single injection of VIPhyb was more effective than multiple doses in achieving long-term tumor-free survival, with 60% survival among C1498-tumor bearing mice (p<0.01 vs. controls, n=5) treated with 3 doses, and 46% survival in mice (p<0.01 vs. control, n=13) with C1498 and 40% survival in mice (p=0.06 vs. control, n=5,) with LBRM treated with 7 doses. None of the control mice inoculated with C1498 (n=21) or LBRM (n=10) that received PBS injections survived to day 55. To explore the therapeutic effect of VIPhyb on established tumors, B6 mice and B10BR were treated with 7 daily doses of VIPhyb starting 8 days or 15 days after inoculation with Luc+ C1498 or Luc+ LBRM, respectively. Survival of B6 mice bearing C1498 and B10BR mice bearing LBRM that received delayed administration of VIPhyb was 60% (p<0.001 vs. control, n=10) and 20% (p=0.039 vs. control, n=5), respectively, compared with 0 % survival (and faster tumor growth) among control mice (B6 n=10; B10BR n=5) that received PBS injections. Tumor burdens in VIPhyb treated mice measured by BLI showed slower tumor growth, and regression of established tumors compared with mice that received PBS (Figure 1). To elucidate the mechanisms whereby VIPhyb induced anti-tumor activities, expression of serum cytokines (IFN-γ, TNF-α, IL-10 and IL-13), expression of co-inhibitory molecules PD-1, PD-1H, PD-L1, and effector molecules Fas-L and granzyme B were measured in T-cells from VIPhyb- and PBS-treated tumor-bearing B10BR mice. Blood and splenic activated (CD62L-CD25+CD69+) and memory (CD62L+/-CD44+) CD8+ T-cells from VIPhyb-treated tumor–bearing mice expressed higher levels of IFN-γ, FAS-L and granzyme B, and lower levels of PD-1 (but not VISTA/PD-1H) in activated CD8+ T-cells compared with those from PBS-treated mice (Figure 2). Expression levels of TNF-α, IL-10, IL-13, and PD-L1 in blood and splenic dendritic cells were not different comparing with tumor-bearing VIPhyb-treated with PBS-treated control mice. Conclusion Treatment with a small molecule antagonist of VIP-receptor, VIPhyb, dramatically increased immune/T-cell specific anti-leukemic activity. The mechanism by which administration of a VIP receptor antagonist enhanced anti-tumor immunity includes increasing productions of IFN-γ, and expression of FAS-L and granzyme B in and decreasing expression of PD-1 in activated CD8+ T-cells, leading to enhance anti-tumor cytotoxicity. Disclosures: No relevant conflicts of interest to declare.

scholarly journals 208 RTX-224, an engineered allogeneic red cell therapeutic expressing 4–1BBL and IL-12, activates immune cells in blood and spleen to promote tumor growth inhibition in mice

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A219-A219
Author(s):  
Anne-Sophie Dugast ◽  
Shannon McArdel ◽  
Zafira Castano ◽  
Maegan Hoover ◽  
Arjun Reddy Bollampalli ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Nk Cells ◽  
Mechanism Of Action ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cell Types ◽  
Tumor Growth Inhibition ◽  
Tumor Bearing

BackgroundAgonist antibodies and recombinant cytokines have had limited success in the clinic due to three factors: severe toxicity leading to a narrow therapeutic index, the diminished activity of an agonistic antibody compared with natural ligand, and the lack of multiple signals needed to effectively activate most cell types. To address these limitations, Rubius Therapeutics has developed RTX-224, an allogeneic red cell therapeutic genetically engineered to express hundreds of thousands of copies of 4-1BBL and IL-12 in their natural conformation on the cell surface. RTX-224 is designed to activate four key target cell types: CD4+ and CD8+ T cells, antigen presenting cells and NK cells for a broad and effective anti-tumor response while providing improved safety due to the restricted biodistribution of red blood cells to the vasculature and spleen. Here we investigated the potential efficacy and mechanism of action of RTX-224 using the mouse surrogate mRBC-224.MethodsmRBC-224 was administered intravenously (i.v.) to normal or tumor-bearing mice (B16F10 tumor models). Blood, spleen and tumors were harvested and the pharmacodynamic effects of mRBC-224 on immune cells were evaluated.ResultsmRBC-224 administered to mice inoculated i.v. with B16F10 melanoma reduced the number of metastases (p<0.0001 and 76.8% tumor growth inhibition on Day 14). This was accompanied by increased proliferation (Ki67+) and cytotoxicity (GzmB+) of tumor-infiltrating CD8+ T cells and NK cells, and an increased CD8+ effector memory (TEM) phenotype. Similarly, mRBC-224 reduced tumor growth in the B16F10 s.c. model (p<0.0001 and 56.2% tumor growth inhibition on Day 9), and this was associated with increased frequency of activated (MHC-II+) tumor-infiltrating macrophages. Consistent with the known biodistribution of red cells, mRBC-224 did not distribute to the tumor but was predominantly localized in the blood and spleen raising the question about mRBC-224 mechanism of action in mediating antitumor responses. In normal and B16F10 s.c. tumor-bearing mice, mRBC-224 induced the activation of CD8+ T cells, NK cells and monocytes/macrophages in blood and spleen in a dose-dependent manner. PD studies in the tumor suggest that these activated immune cells are capable of trafficking from blood/spleen to the tumor. These results align with published data suggesting that activated T cells in the spleen or blood can replenish exhausted tumor-infiltrating cells.ConclusionsTaken together, these data unveil the mechanism of action of mRBC-224 and suggest that mRBC-224 activate immune cells in the spleen and blood, leading to their trafficking into the tumor microenvironment to promote efficacy.

scholarly journals Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

2021 ◽  
Vol 22 (10) ◽  
pp. 5207
Author(s):  
Chi Yan ◽  
Jinming Yang ◽  
Nabil Saleh ◽  
Sheau-Chiann Chen ◽  
Gregory D. Ayers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mtor Pathway ◽  
Complete Regression ◽  
Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

scholarly journals Digital Immunophenotyping Predicts Disease Free and Overall Survival in Early Stage Melanoma Patients

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 422
Author(s):  
Francesco De Logu ◽  
Francesca Galli ◽  
Romina Nassini ◽  
Filippo Ugolini ◽  
Sara Simi ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Cd8 T Cells ◽  
Early Stage ◽  
High Density ◽  
Stage Ii ◽  
Prognostic Impact ◽  
Training Cohort ◽  
Melanoma Patients ◽  
Disease Free

Background: the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and spatial distribution of immune cells in early stage intermediate/thick PCM. Materials and Methods: digital image acquisition and quantitative analysis of tissue immune biomarkers (CD3, CD4, CD8, CD68, PD-L1, CD163, FOX-P3, and PD-1) was carried out in a training cohort, which included patients with primary PCM ≥ 2 mm diagnosed, treated, and followed-up prospectively in three Italian centers. Results were validated in an independent Italian cohort. Results: in the training cohort, 100 Stage II–III melanoma patients were valuable. At multivariable analysis, a longer disease free survival (DFS) was statistically associated with higher levels of CD4+ intratumoral T-cells (aHR [100 cell/mm2 increase] 0.98, 95%CI 0.95–1.00, p = 0.041) and CD163+ inner peritumoral (aHR [high vs. low] 0.56, 95%CI 0.32–0.99, p = 0.047). A statistically significant longer DFS (aHR [high-high vs. low-low] 0.52, 95%CI 0.28–0.99, p = 0.047) and overall survival (OS) (aHR [high-high vs. low-low] 0.39, 95%CI 0.18–0.85, p = 0.018) was found in patients with a high density of both intratumoral CD8+ T-cells and CD68+ macrophages as compared to those with low density of both intratumoral CD8+ T-cells and CD68+ macrophages. Consistently, in the validation cohort, patients with high density of both intratumoral CD8+ and CD3+ T-cells were associated to a statistically better DFS (aHR[high-high vs. low-low] 0.24, 95%CI 0.10–0.56, p < 0.001) and those with high density of both intratumoral CD8+ and CD68+ were associated to a statistically longer OS (aHR[high-high vs. low-low] 0.28, 95%CI 0.09–0.86, p = 0.025). Conclusion: our findings suggest that a specific preexisting profile of T cells and macrophages distribution in melanomas may predict the risk of recurrence and death with potential implications for the stratification of stage II–III melanoma patients.

scholarly journals Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 870
Author(s):  
Tomasz M. Grzywa ◽  
Magdalena Justyniarska ◽  
Dominika Nowis ◽  
Jakub Golab
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Progenitor Cells ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Interleukin 10 ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

Transgenic expression of IL-33 activates CD8+ T cells and NK cells and inhibits tumor growth and metastasis in mice

2013 ◽  
Vol 335 (2) ◽  
pp. 463-471 ◽  
Author(s):  
Kun Gao ◽  
Xiaoying Li ◽  
Li Zhang ◽  
Lin Bai ◽  
Wei Dong ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Transgenic Expression ◽  
Tumor Growth And Metastasis

scholarly journals Tumor and Peripheral Immune Status in Soft Tissue Sarcoma: Implications for Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3885
Author(s):  
Luana Madalena Sousa ◽  
Jani Sofia Almeida ◽  
Tânia Fortes-Andrade ◽  
Manuel Santos-Rosa ◽  
Paulo Freitas-Tavares ◽  
...  
Keyword(s):  
T Cells ◽  
Soft Tissue ◽  
Cd8 T Cells ◽  
Soft Tissue Sarcomas ◽  
Suppressor Cells ◽  
Response To Therapy ◽  
Immune Checkpoints ◽  
Soluble Factors ◽  
Lymphocyte To Monocyte Ratio ◽  
Immune Related Genes

Soft Tissue Sarcomas (STS) are a heterogeneous and rare group of tumors. Immune cells, soluble factors, and immune checkpoints are key elements of the complex tumor microenvironment. Monitoring these elements could be used to predict the outcome of the disease, the response to therapy, and lead to the development of new immunotherapeutic approaches. Tumor-infiltrating B cells, Natural Killer (NK) cells, tumor-associated neutrophils (TANs), and dendritic cells (DCs) were associated with a better outcome. On the contrary, tumor-associated macrophages (TAMs) were correlated with a poor outcome. The evaluation of peripheral blood immunological status in STS could also be important and is still underexplored. The increased lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR), higher levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and Tim-3 positive CD8 T cells appear to be negative prognostic markers. Meanwhile, NKG2D-positive CD8 T cells were correlated with a better outcome. Some soluble factors, such as cytokines, chemokines, growth factors, and immune checkpoints were associated with the prognosis. Similarly, the expression of immune-related genes in STS was also reviewed. Despite these efforts, only very little is known, and much research is still needed to clarify the role of the immune system in STS.

scholarly journals Role of CD4+ CD25+ FOXP3+ regulatory T-cells and human papilloma virus infection in Egyptian Women with breast cancer

2019 ◽  
Author(s):  
Amany Tawfeik ◽  
Ahmed Mora ◽  
Ahmed Osman ◽  
Nabila Elsheikh ◽  
Mohamed Elrefaei
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
High Risk ◽  
Human Papilloma Virus ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Early Stage ◽  
Significant Proportion ◽  
Papilloma Virus ◽  
Egyptian Women

Abstract Several subsets of regulatory CD4+ T cells (CD4+ Tregs) have been described in peripheral blood and tumor microenvironment and blood of breast cancer (BC) patients and may play a key role in the progression of BC. High-risk human papilloma virus (HPV) have a causal role in a significant proportion of cervical, and head, and neck tumors and may play an important role in evoking neoplasia in BC. In this study we assessed the prevalence of CD4+Tregs (CD4+CD25+ FOXP3+ cells) and CD8+T cells by flow cytometry in peripheral blood from a total of 55 Egyptian women, including 20 treatment-naïve BC, 15 with breast benign lesions (BBL) and 20 healthy volunteers (HV). High-risk HPV genotype type 16, 18, and 31 was investigated in breast tissue from all BC and BBL patients using Real-Time PCR. HPV was detected in 4 BC, but in none of BBL patients. The frequency of CD4+ Tregs was significantly higher in BC compared to BBL and HV, (p < 0.001). In addition, we observed a significantly higher frequency of CD8+ T cells in peripheral blood of patients with late stage III compared to early stage I and II BC (p = 0.011). However, there was no significant association between the ratio of CD8+ T cell to CD4+ Tregs frequencies and the expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). In conclusion, CD4+ Tregs may contribute to progression BC in Egyptian women with HPV infection. The potential role CD4+ Tregs as a prognostic or predictive parameter should be analyzed in a larger longitudinal study with sufficient follow-up time.

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