scholarly journals The CCR2/MCP-1 Chemokine Pathway and Lung Adenocarcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3723
Author(s):  
Payal Mittal ◽  
Liqing Wang ◽  
Tatiana Akimova ◽  
Craig A. Leach ◽  
Jose C. Clemente ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Suppressor Cells ◽  
Treg Cells ◽  
Cancer Models ◽  
Inflammatory Site ◽  
Ccr2 Antagonist

Host anti-tumor immunity can be hindered by various mechanisms present within the tumor microenvironment, including the actions of myeloid-derived suppressor cells (MDSCs). We investigated the role of the CCR2/MCP-1 pathway in MDSC-associated tumor progression in murine lung cancer models. Phenotypic profiling revealed maximal expression of CCR2 by tumor-resident MDSCs, and MCP-1 by transplanted TC1 tumor cells, respectively. Use of CCR2-knockout (CCR2-KO) mice showed dependence of tumor growth on CCR2 signaling. Tumors in CCR2-KO mice had fewer CCR2low MDSCs, CD4 T cells and Tregs than WT mice, and increased infiltration by CD8 T cells producing IFN-γ and granzyme-B. Effects were MDSC specific, since WT and CCR2-KO conventional T (Tcon) cells had comparable proliferation and production of inflammatory cytokines, and suppressive functions of WT and CCR2-KO Foxp3+ Treg cells were also similar. We used a thioglycolate-induced peritonitis model to demonstrate a role for CCR2/MCP-1 in trafficking of CCR2+ cells to an inflammatory site, and showed the ability of a CCR2 antagonist to inhibit such trafficking. Use of this CCR2 antagonist promoted anti-tumor immunity and limited tumor growth. In summary, tumor cells are the prime source of MCP-1 that promotes MDSC recruitment, and our genetic and pharmacologic data demonstrate that CCR2 targeting may be an important component of cancer immunotherapy.

scholarly journals Knockout of High-Mobility Group Box 1 in B16F10 Melanoma Cells Induced Host Immunity-Mediated Suppression of In Vivo Tumor Growth

2021 ◽  
Author(s):  
Kanako Yokomizo ◽  
Kayoko Waki ◽  
Miyako Ozawa ◽  
Keiko Yamamoto ◽  
Sachiko Ogasawara ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
High Mobility

Abstract High mobility group box 1 (HMGB1) has been reported as a damage-associated molecular pattern (DAMP) molecule that is released from damaged or dead cells and induces inflammation and subsequent innate immunity. However, the role of HMGB1 in the anti-tumor immunity is unclear since inflammation in the tumor microenvironment also contributes to tumor promotion and progression. In the present study, we established HMGB1-knockout clones from B16F10 and CT26 murine tumors by genome editing using the CRISPR/Cas9 system and investigated the role of HMGB1 in anti-tumor immunity. We found that 1) knockout of HMGB1 in the tumor cells suppressed in vivo, but not in vitro, tumor growth, 2) the suppression of the in vivo tumor growth was mediated by CD8 T cells, and 3) infiltration of CD8 T cells, macrophages and dendritic cells into the tumor tissues was accelerated in HMGB1-knockout tumors. These results demonstrated that knockout of HMGB1 in tumor cells converted tumors from poor infiltration of immune cells called “cold” to “immune-inflamed” or “hot” and inhibited in vivo tumor growth mediated by cytotoxic T lymphocytes. Infiltration of immune cells to the tumor microenvironment is an important step in the series known as the cancer immunity cycle. Thus, manipulation of tumor-derived HMGB1 might be applicable to improve the clinical outcomes of cancer immunotherapies, including immune checkpoint blockades and cancer vaccine therapies.

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 Tumor Immune Microenvironment and Its Related miRNAs in Tumor Progression

2021 ◽  
Vol 12 ◽  
Author(s):  
Yingying Xing ◽  
Guojing Ruan ◽  
Haiwei Ni ◽  
Hai Qin ◽  
Simiao Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Immune Cells ◽  
Suppressor Cells ◽  
Immune Microenvironment ◽  
Non Coding Rna ◽  
Tumor Immune Microenvironment ◽  
Downstream Gene Expression

MiRNA is a type of small non-coding RNA, by regulating downstream gene expression that affects the progression of multiple diseases, especially cancer. MiRNA can participate in the biological processes of tumor, including proliferation, invasion and escape, and exhibit tumor enhancement or inhibition. The tumor immune microenvironment contains numerous immune cells. These cells include lymphocytes with tumor suppressor effects such as CD8+ T cells and natural killer cells, as well as some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells. MiRNA can affect the tumor immune microenvironment by regulating the function of immune cells, which in turn modulates the progression of tumor cells. Investigating the role of miRNA in regulating the tumor immune microenvironment will help elucidate the specific mechanisms of interaction between immune cells and tumor cells, and may facilitate the use of miRNA as a predictor of immune disorders in tumor progression. This review summarizes the multifarious roles of miRNA in tumor progression through regulation of the tumor immune microenvironment, and provides guidance for the development of miRNA drugs to treat tumors and for the use of miRNA as an auxiliary means in tumor immunotherapy.

scholarly journals Two novel human anti-CD25 antibodies with antitumor activity inversely related to their affinity and in vitro activity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Deyong Song ◽  
Xiu Liu ◽  
Chuangchuang Dong ◽  
Qiaoping Wang ◽  
Chunjie Sha ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Treg Cells ◽  
Tumor Growth Inhibition ◽  
In Vitro Activity ◽  
Limited Efficacy ◽  
Cancer Models ◽  
Excellent Candidate

AbstractHigh tumor regulatory T (Treg) cell infiltration is associated with poor prognosis of many cancers. CD25 is highly expressed on tumor Treg cells and is a potential target for Treg deletion. Previously characterized anti-CD25 antibodies appear to have limited efficacy in tumor inhibition. Here we identified two human anti-CD25 antibodies, BA9 and BT942, which did not prevent the activation of IL-2R signaling pathway by IL-2. BT942 had weaker binding and cytotoxic activity to human CD25-expressing cell lines than BA9. But both demonstrated significant tumor growth inhibition in early and late-stage animal cancer models. BT942 resulted in a higher expansion of CD8+ T cells and CD4+ T cells in tumor microenvironment in mouse MC38 model compared to BA9. BT942 also demonstrated significant higher tumor growth inhibition and higher expansion of CD8+ T cells and CD4+ T cells in combination with an anti-PD1 antibody. Pharmacokinetic study of BT942 in cynomolgus monkeys demonstrated a half-life of 206.97 ± 19.03 h. Structural analysis by cryo-EM revealed that BT942 recognizes an epitope on opposite side of the CD25-IL-2 binding site, consistent with no IL-2 signaling blockade in vitro. BT942 appears to be an excellent candidate for cancer immunotherapy.

scholarly journals Two Novel Human Anti-cd25 Antibodies With Antitumor Activity Inversely Related to Its Affinity and in Vitro Activity

2021 ◽  
Author(s):  
Deyong Song ◽  
Xiu Liu ◽  
Chuangchuang Dong ◽  
Chunjie Sha ◽  
Zhenfei Ning ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Treg Cells ◽  
Tumor Growth Inhibition ◽  
In Vitro Activity ◽  
Limited Efficacy ◽  
Cancer Models ◽  
Excellent Candidate

Abstract High tumor regulatory T (Treg) cell infiltration is associated with poor prognosis of many cancers. CD25 is highly expressed on tumor Treg cells and is a potential target for Treg deletion. Previously characterized anti-CD25 antibodies appear to have limited efficacy. Here we identified two human anti-CD25 antibodies, BA9 and BT942, which demonstrated strong tumor growth inhibition in both early and late-stage animal cancer models. BT942 had weaker binding and cytotoxic activity to human CD25-expressing cell lines than BA9. But BT942 showed a stronger anti-tumor effect and resulted a higher expansion of CD8+ T cells and CD4+ T cells in tumor microenvironment at the mouse MC38 model compared to BA9. As CD25 is transiently expressed on activated Teff cells, it is likely that BT942 with lower affinity can distinguish high expression Treg and low expression Teff and therefore cannot kill Teff cells effectively. Such a combination of BT942’s abilities may underline its stronger effect. BT942 also demonstrated higher tumor growth inhibition in combination with an anti-PD1 antibody. Pharmacokinetic tests of BT942 in cynomolgus monkey demonstrated a half-life of 206.97±19.03 hours. No toxicity efficacy was seen in mice efficacy or monkey examinations. BT942 appears to be an excellent candidate for cancer immunotherapy.

scholarly journals Lactate Increases Stemness of CD8+ T Cells to Augment Anti-Tumor Immunity

2021 ◽  
Author(s):  
Qiang Feng ◽  
Zhida Liu ◽  
Xuexin Yu ◽  
Tongyi Huang ◽  
Jiahui Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Subcutaneous Administration ◽  
Tumor Growth Inhibition ◽  
Mouse Splenocytes

Nutrients and metabolites play important roles in immune functions. Recent studies show lactate instead of glucose can serve as a primary carbon fuel source for most tissues. The role of lactate in tumor immunity is not well understood with immune suppressive functions reported for lactic acid, the conjugate acid form of lactate. In this study, we report lactate increases the stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of lactate but not glucose shows CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis revealed lactate treatment increased a subpopulation of stem-like TCF-1-expressing CD8+ T cells, which is further validated by ex vivo culture of CD8+ T cells from mouse splenocytes and human peripheral blood mononuclear cells. The inhibition of histone deacetylase activity by lactate increased acetylation in the histone H3K27 site at the Tcf7 super enhancer locus and increased the gene expression of Tcf7. Adoptive transfer of CD8+ T cells pretreated with lactate in vitro showed potent tumor growth inhibition in vivo. Our results elucidate the immune protective role of lactate in anti-tumor immunity without the masking effect of acid. These results may have broad implications for T cell therapy and the understanding of lactate in immune metabolism.

Accumulation of Myeloid-Derived Suppressor Cells in Bone Marrow in Multiple Myeloma Induces Tumor-Specific Immune Suppression and Promotes Tumor Growth

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3954-3954
Author(s):  
Indu R Ramachandran ◽  
Anna Martner ◽  
Thomas C Condamine ◽  
Alexandra Pisklakova ◽  
Tess Chase ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Growth ◽  
Suppressor Cells ◽  
Cell Responses ◽  
Healthy Donors ◽  
Immature Myeloid Cells ◽  
Time Point

Abstract Abstract 3954 Multiple myeloma (MM) is an incurable malignancy of clonal plasma cells in bone marrow (BM). Accumulation of MM cells in BM is associated with a corresponding dysfunction of local immune responses. The mechanisms involved in the immune suppression remains poorly understood. Myeloid-derived suppressor cells (MDSC) are heterogeneous group of relatively immature myeloid cells characterized by potent immune suppressive activity. However, their role in regulation of immune responses in BM in MM remains unclear. To determine MDSC accumulation in MM patients, BM and blood samples were obtained from newly diagnosed patients and healthy donors. We observed a significant increase in CD11b+ CD33+ CD14− HLA-DRlo MDSCs, but not in CD11b+ CD33+ CD14+ HLA-DRhi monocytes, in the blood and BM of patients as compared to cells with the same phenotype in healthy donors. MDSC isolated from patient BM suppressed T cell responses as measured by IFN-g Elispot assays of mixed leukocyte reactions. Immature myeloid cells with the same phenotype from BM of healthy donor did not inhibit T cells. The possible role of MDSC in MM progression was further evaluated in mouse model of MM. Three different MM cell lines (BCM, DP42 and ATLN) obtained from Dr Van Ness (University of Minnesota) were used. MM tumors were established by i.v. injection of syngeneic mice. We observed an expansion of CD11b+ GR1+ MDSCs (up to 70%) in the BM of tumor-bearing (TB) mice within one week after injection of tumor cells. MDSC purified from BM of TB mice at that time point potently suppressed antigen-specific T cell proliferation and IFN-g production. As tumor progressed, CD138+ MM cells expanded (up to 90%) in the BM replacing normal BM cells including MDSC. However, at later time points (2–3 weeks), MDSC expansion was seen in spleen and lymph nodes of TB mice. To evaluate the possible role of MDSC in MM progression, we used S100A9 knockout (KO) mice. S100A9 plays an important role in MDSC accumulation in cancer and S100A9 KO TB mice had reduced accumulation of these cells. When wild-type (WT) and S100A9 KO mice were inoculated with DP42 cells no differences in tumor growth and survival were observed. S100A9 KO mice had a decrease in MDSC accumulation in the BM of TB mice compared to WT mice. Additionally, MDSC from S100A9 KO mice failed to suppress antigen-specific T cells ex vivo, whereas MDSC from WT TB mice did. To evaluate the development of antigen-specific immune responses in MM, we generated a MM cell line over-expressing the chicken ovalbumin protein (DP42-OVA). S100A9 KO mice injected with the immunogenic DP42-OVA cell line showed significantly delayed tumor growth and improved survival as compared with WT mice. Further analysis of T cell responses in vivo showed increased accumulation of antigen-specific T cells within the BM of S100A9 KO mice, but not WT mice, as early as one week post-tumor inoculation. Antigen-specific T cells in spleens were not detected at that time point. These cells were seen in spleens on S100A9 KO mice only 2–3 weeks after tumor injection. Thus, our study demonstrated that MM is associated with rapid accumulation of MDSC with potent immune suppressive activity against tumor-specific T cells. Our data directly suggest that targeting MDSC in MM may improve antitumor immune response and clinical outcome of the disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals AGI-134: a fully synthetic α-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Stephen M. Shaw ◽  
Jenny Middleton ◽  
Kim Wigglesworth ◽  
Amber Charlemagne ◽  
Oliver Schulz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Tumor Antigen ◽  
Tumor Regression ◽  
Antigen Uptake

Abstract Background Treatments that generate T cell-mediated immunity to a patient’s unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galα1-3Galβ1-4GlcNAc (α-Gal) in situ leading to opsonization with pre-existing natural anti-α-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity. Methods Various immunological effects of coating tumor cells with α-Gal via AGI-134 in vitro were measured by flow cytometry: (1) opsonization with anti-Gal and complement, (2) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and (3) phagocytosis and antigen cross-presentation by antigen presenting cells (APCs). A viability kit was used to test AGI-134 mediated complement dependent cytotoxicity (CDC) in cancer cells. The anti-tumoral activity of AGI-134 alone or in combination with an anti-programmed death-1 (anti-PD-1) antibody was tested in melanoma models in anti-Gal expressing galactosyltransferase knockout (α1,3GT−/−) mice. CDC and phagocytosis data were analyzed by one-way ANOVA, ADCC results by paired t-test, distal tumor growth by Mantel–Cox test, C5a data by Mann–Whitney test, and single tumor regression by repeated measures analysis. Results In vitro, α-Gal labelling of tumor cells via AGI-134 incorporation into the cell membrane leads to anti-Gal binding and complement activation. Through the effects of complement and ADCC, tumor cells are lysed and tumor antigen uptake by APCs increased. Antigen associated with lysed cells is cross-presented by CD8α+ dendritic cells leading to activation of antigen-specific CD8+ T cells. In B16-F10 or JB/RH melanoma models in α1,3GT−/− mice, intratumoral AGI-134 administration leads to primary tumor regression and has a robust abscopal effect, i.e., it protects from the development of distal, uninjected lesions. Combinations of AGI-134 and anti-PD-1 antibody shows a synergistic benefit in protection from secondary tumor growth. Conclusions We have identified AGI-134 as an immunotherapeutic drug candidate, which could be an excellent combination partner for anti-PD-1 therapy, by facilitating tumor antigen processing and increasing the repertoire of tumor-specific T cells prior to anti-PD-1 treatment.

scholarly journals CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1935
Author(s):  
Julie Vackova ◽  
Ingrid Polakova ◽  
Shweta Dilip Johari ◽  
Michal Smahel
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Cell Subset ◽  
Treg Cells ◽  
Lymphoid Cells ◽  
Induced Tumors

Cluster of differentiation (CD) 80 is mainly expressed in immune cells but can also be found in several types of cancer cells. This molecule may either activate or inhibit immune reactions. Here, we determined the immunosuppressive role of CD80 in the tumor microenvironment by CRISPR/Cas9-mediated deactivation of the corresponding gene in the mouse oncogenic TC-1 cell line. The tumor cells with deactivated CD80 (TC-1/dCD80-1) were more immunogenic than parental cells and induced tumors that gained sensitivity to cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade, as compared with the TC-1 cells. In vivo depletion experiments showed that the deactivation of CD80 switched the pro-tumorigenic effect of macrophages observed in TC-1-induced tumors into an anti-tumorigenic effect in TC-1/dCD80-1 tumors and induced the pro-tumorigenic activity of CD4+ cells. Moreover, the frequency of lymphoid and myeloid cells and the CTLA-4 expression by T helper (Th)17 cells were increased in TC-1/dCD80-1- compared with that in the TC-1-induced tumors. CTLA-4 blockade downregulated the frequencies of most immune cell types and upregulated the frequency of M2 macrophages in the TC-1 tumors, while it increased the frequency of lymphoid cells in TC-1/dCD80-1-induced tumors. Furthermore, the anti-CTLA-4 therapy enhanced the frequency of CD8+ T cells as well as CD4+ T cells, especially for a Th1 subset. Regulatory T cells (Treg) formed the most abundant CD4+ T cell subset in untreated tumors. The anti-CTLA-4 treatment downregulated the frequency of Treg cells with limited immunosuppressive potential in the TC-1 tumors, whereas it enriched this type of Treg cells and decreased the Treg cells with high immunosuppressive potential in TC-1/dCD80-1-induced tumors. The immunosuppressive role of tumor-cell-expressed CD80 should be considered in research into biomarkers for the prediction of cancer patients’ sensitivity to immune checkpoint inhibitors and for the development of a tumor-cell-specific CD80 blockade.

scholarly journals Integrin αvβ8 on T cells is responsible for suppression of anti-tumor immunity in multiple syngeneic models and is a promising target for tumor immunotherapy

2020 ◽  
Author(s):  
Eswari Dodagatta-Marri ◽  
Hsiao-Yen Ma ◽  
Benjia Liang ◽  
John Li ◽  
Dominique S. Meyer ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Immune Checkpoint Blockade ◽  
Complete Regression ◽  
Promising Target

AbstractThe αvβ8 integrin is a key activator of transforming growth factor β (TGF β), which has been shown to inhibit anti-tumor immunity. Previous work has suggested that αvβ8 on tumor cells could modulate tumor growth and responses to immune checkpoint blockade. We now show that a potent blocking monoclonal antibody against αvβ8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma (CCK168), mammary cancer (EMT-6), colon cancer (CT26), and prostate cancer (TRAMPC2), especially when it is combined with other immunomodulators (anti-PD-1, anti-CTLA-4 or 4-1BB) or radiotherapy. αvβ8 is expressed on tumor cells in some of these models, but tumor cell expression of αvβ8 is not essential for the beneficial effects of ADWA-11 therapy. αvβ8 is consistently expressed at highest levels on CD4+CD25+ T cells within tumors, and specific deletion of Itgb8 from T cells is as effective as ADWA-11 in suppressing tumor growth. Treatment with ADWA-11 increases expression of a suite of genes in tumor infiltrating CD8+ T cells that are normally inhibited by TGFβ and are involved in tumor cell killing, including Granzyme B and Interferon-γ. These findings solidify αvβ8 integrin as a promising target for cancer immunotherapy, even for tumors that do not express this integrin.

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