scholarly journals Activation of GM-CSF and TLR2 signaling synergistically enhances antigen-specific antitumor immunity and modulates the tumor microenvironment

2021 ◽  
Vol 9 (10) ◽  
pp. e002758
Author(s):  
Wan-Lun Yan ◽  
Chiao-Chieh Wu ◽  
Kuan-Yin Shen ◽  
Shih-Jen Liu
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Antitumor Immunity ◽  
Synergistic Effects ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Toll Like Receptor ◽  
Tlr2 Agonist ◽  
Gm Csf

BackgroundThe major challenge of antitumor immunotherapy is dealing with the immunosuppressive tumor microenvironment, which involves immature myeloid cell accumulation that results in T cell dysfunction. Myeloid cell activation is induced by Toll-like receptor agonists. Additionally, granulocyte/macrophage colony stimulating factor (GM-CSF) promotes myelopoiesis and recruits myeloid cells. Here, we combined the Toll-like receptor 2 (TLR2) agonist lipoprotein and GM-CSF to assess whether this bifunctional immunotherapy has synergistic effects on myeloid cells and could be further developed as a therapeutic intervention that enhances the antitumor response.MethodsWe investigated the synergistic effects of biadjuvanted tumor antigen on antigen-presenting cell (APC) activation in bone marrow-derived dendritic cells. Furthermore, therapeutic efficacy was monitored in different tumor models treated via intratumoral or subcutaneous administration routes. The immune effects of the bifunctional fusion protein on myeloid cells in the tumor mass and draining lymph nodes were analyzed by flow cytometry. The induction of cytotoxic T lymphocytes was evaluated via intracellular cytokine levels, perforin/granzyme B staining and an in vivo killing assay.ResultsThe TLR2 agonist lipoprotein combined with GM-CSF synergistically induced DC maturation, which subsequently enhanced antitumor immunity. In addition, rlipoE7m-MoGM modulated tumor-infiltrating myeloid cell populations. Vaccination with rlipoE7m-MoGM therapy increased the number of CCR7+CD103+ cDC1s, whereas the number of suppressive tumor-associated macrophages was reduced in the tumor lesions. Consistent with this observation, proliferating antigen-specific CD8+ T cells are highly infiltrated within the tumor, and the expression of IFN-r and perforin was most pronounced within antigen-specific CD8+ T cells in mice administered rlipoE7m-MoGM therapy. This finding corresponded with observation that the combination of a TLR2 agonist and GM-CSF provides increased antitumor activity by inhibiting established tumor outgrowth and protecting against metastatic cancer compared with a TLR2 agonist alone. Importantly, tumor growth inhibition was not due to the direct effects of the TLR2 agonist or GM-CSF but was instead due to the induction of antigen-specific immunity.ConclusionsThe combination of a TLR2 agonist and GM-CSF has synergistic effects that inhibit tumor growth and modulate tumor-infiltrating APCs. This therapeutic approach could be applied to other tumor antigens to treat different cancers.

Vaccination With Irradiated Induced Pluripotent Stem Cells Genetically Engineered To Produce GM-CSF Confers Potent T Cells-Mediated Antitumor Immunity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4492-4492 ◽  
Author(s):  
Hiroyuki Inoue ◽  
Ayumi Watanabe ◽  
Chika Sakamoto ◽  
Megumi Narusawa ◽  
Takafumi Hiramoto ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Antitumor Immunity ◽  
Es Cells ◽  
Ips Cells ◽  
Genetically Engineered ◽  
Antitumor Effects ◽  
Gm Csf ◽  
Csf Cells

Development of a novel therapeutic modality targeting cancer stem cells (CSCs) holds great promise for the eventual eradication of cancer. It was demonstrated that CSCs shared antigenic similarities with embryonic stem (ES) cells and the vaccination using ES cells could generate antitumor immunity. However, the use of ES cells raises potential immunological and ethical problematic issues. Recently, by the forced ectopic expression of defined transcription factors, autologous somatic cells were successfully reprogrammed into induced pluripotent stem (iPS) cells that closely resemble ESCs. We hypothesized that novel cell vaccines using mouse iPS cells genetically engineered to express the immunostimulatory cytokine of GM-CSF would cross-react CSC cells to induce antitumor immunity against poorly immunogenic syngeneic LLC mouse lung cancer cells, which would resolve such problematic issues. Our results of in vitro assays demonstrated that non-transmissible recombinant Sendai virus-mediated mouse GM-CSF gene transfer to iPSCs (iPS/GM-CSF) was effective to produce abundant GM-CSF in vitro and iPS/GM-CSF cells maintained their stemness in terms of morphology and antigenicity as evidenced by the expression of SSEA-1,Oct3/4 and alkaline phosphatase compared with unmodified iPS cells. Prophylactic iPSCs vaccine studies revealed that wild-type female mice subcutaneously vaccinated with irradiated iPS (ir.iPS) cells on weeks 1, 2, and 3 before the tumor challenge with LLC cells significantly suppressed the LLC tumor growth compared with untreated mice (p<0.05). Additionally, mice vaccinated with ir.iPS/GM-CSF cells significantly inhibited the tumor growth compared with mice treated with ir.iPS/GFP cells (p<0.05), showing that genetic manipulation of iPS cells with GM-CSF encoding gene potentiated the antitumor effect. Of note, no serious adverse events were observed with lack of liver and kidney dysfunctions as evidenced by biochemical analysis. Furthermore, therapeutic vaccinations with repeated ir.iPS/GM-CSF cells significantly inhibited the pre-established LLC tumor growth compared with untreated mice (p<0.05), with unaltered body weight. To address the effectors of the observed antitumor effects by ir.iPS/GM-CSF cells, we performed in vivo depletion experiments. The antitumor effects observed in mice treated with iPS/GM cells were significantly abrogated when CD4+ T cells- or CD8+ T cells were depleted, showing that iPS cells-based vaccines effectively generated T cells-mediated antitumor immunity. Lastly, we performed a cDNA microarray analysis to detect comparably expressed genes for the putative CSCs-associated antigens as a target of iPS cells-based vaccines on LLC cells, iPS cells, ir.iPS cells and ir.iPS/GM-CSF cells. Several sperm- or cell surface- specific antigens were predominantly expressed and shared between LLC cells and these iPS cell fractions, indicating that LLC cells and iPS cells may share CSCs-associated antigens. In conclusion, our results collectively demonstrate iPS cells-based vaccine can induce both prophylactic and therapeutic antitumor immunity in syngeneic mouse models, and indicate that this novel vaccine strategy may eliminate CSCs that shared antigenic similarities as a promising modality for cancer immunotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chimeric Antigen Receptor T Cells Shape Myeloid Cell Function within the Tumor Microenvironment through IFN-γ and GM-CSF

2012 ◽  
Vol 188 (12) ◽  
pp. 6389-6398 ◽  
Author(s):  
Paul Spear ◽  
Amorette Barber ◽  
Agnieszka Rynda-Apple ◽  
Charles L. Sentman
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Chimeric Antigen Receptor ◽  
Cell Function ◽  
Antigen Receptor ◽  
Myeloid Cell ◽  
Gm Csf ◽  
Ifn Γ

scholarly journals Pro-atherogenic diet accelerates tumor growth in mice through IL-1β and myeloid cell-derived VEGF-A

2020 ◽  
Author(s):  
Thi Tran ◽  
Bruno Esposito ◽  
Melanie Montabord ◽  
Jaouen Tran Rajau ◽  
Nadege Gruel ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Solid Tumors ◽  
Immune Cell ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Atherogenic Diet ◽  
Low Grade ◽  
Dependent Manner ◽  
The Metabolic Syndrome

Abstract Aims: Myeloid inflammatory cells are recruited to the tumor microenvironment and subsequently educated in situ to acquire a pro-invasive, pro-angiogenic and immunosuppressive phenotype. Components of the metabolic syndrome are known to aggravate tumorigenesis in part through myeloid cell activation. We hypothesized that consumption of a high fat/high cholesterol pro-atherogenic diet and its associated low-grade inflammation would accelerate the initiation of solid tumors. Methods and results: Here, we show that two-week feeding of wildtype C57BL/6J mice with a pro-atherogenic diet increases the pool of circulating inflammatory Ly-6Chi monocytes available for initial melanoma development and amplifies the accumulation of myeloid cells within the tumor microenvironment, in an IL-1β-dependent manner. Under pro-atherogenic diet feeding, myeloid cells display heightened pro-angiogenic, pro-inflammatory and immunosuppressive activities. Within the first days after tumor implantation, myeloid cells become the main producer of VEGF-A in the tumor. Depletion of Ly-6Chi monocytes in mice fed with a pro-atherogenic diet limits immune cell infiltration in the tumor, and inhibits tumor growth. IL-1β deficiency or specific inhibition of VEGF-A in myeloid cells recapitulates the beneficial effect of Ly-6Chi monocyte depletion, suggesting their complementary roles in tumorigenesis in the context of mild hyperlipidemia. Conclusion: Our study shows that dyslipidemia provide high amounts of activated myeloid cells with pro-tumoral activity and shed light on cross-disease communication between cardiovascular pathologies and cancer. Translational Perspective: In this study we demonstrate that dyslipidemia accelerates the development of solid tumors through the increased infiltration of Ly6Chi monocytes that differentiate into pro-tumoral myeloid cells. These findings demonstrate that dyslipidemia can silently boost tumor development in normal-weight individuals through the action of IL-1β and VEGF-A. Our work sheds light on the potential benefit of targeting IL-1β and VEGF-A in cancer patients with moderate dyslipidemia.

scholarly journals A Combination Therapy with Dendritic Cells, Pomalidomide and Programmed Death-Ligand 1 Blockade Exerts a Potent Antitumor Immunity in a Murine Model of Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1819-1819 ◽  
Author(s):  
Je-Jung Lee ◽  
Tan-Huy Chu ◽  
Manh-Cuong Vo ◽  
Hye-Sung Park ◽  
Thangaraj Jaya Lakshmi ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Tumor Growth ◽  
Antitumor Immunity ◽  
Suppressor Cells ◽  
Cell Mediated Immunity ◽  
M2 Macrophages ◽  
Inhibit Tumor Growth ◽  
Effector Cells

Multiple myeloma (MM) is the second-most-common hematologic malignancy, and develops from clonal malignant plasma cells within bone marrow. Despite tremendous improvements in therapeutic strategies (e.g. stem cell transplantation, immune-modulatory drugs (IMiDs), proteasome inhibitors, and, more recently, immunotherapy), which have led to improved responses to treatment and overall survival, most patients eventually relapse. We have previously shown that the immunization with tumor antigen-loaded dendritic cells (DCs) and pomalidomide/dexamethasone synergistically potentiates the enhancing the antitumor immunity in a myeloma mouse model. In the present study, we investigated whether a DC-based vaccine combined with pomalidomide and PD-L1 blockade has a synergistic effect in a murine MM model. MOPC-315 cell lines were injected subcutaneously to establish MM-bearing mice. Four test groups were used to mimic the clinical protocol: (1) PBS control, (2) DCs + pomalidomide/dexamethasone, (3) pomalidomide/dexamethasone + PD-L1 blockade, and (4) DCs + pomalidomide/dexamethasone + PD-L1 blockade. After treatment, preclinical response and in vitro immunological responses were evaluated. The study was designed to closely mimic the clinical MM treatment protocol and clearly demonstrated that combination treatment with DCs + pomalidomide with dexamethasone + PD-L1 blockade more strongly inhibited MM tumor growth. Consequently, the mice treated with DCs + pomalidomide with dexamethasone + PD-L1 blockade displayed markedly induced tumor regression and significantly prolonged survival, as well as very strong anti-myeloma CTL responses and increased numbers of effector cells (such as CD4+ T cells, CD8+ T cells, memory T cells, NK cells and M1 macrophages) associated with antitumor effects. This treatment also effectively decreased the proportions of suppressor cells, including MDSCs, Tregs and M2 macrophages, in the spleen and tumor microenvironment of treated mice. Tregs, MDSCs and M2 macrophages play crucial roles in immunosuppression and tolerance, which are mediated by tumor-secreted cytokines. The inhibition of Tregs, MDSC and M2 macrophage accumulation may enhance systemic cell-mediated immunity through the activation of DCs or CTLs. Importantly, treatment with pomalidomide with dexamethasone + PD-L1 blockade led to decreased expression of PD-L1 and CTLA-4 in treated mice, which further induced effector cell infiltration of the tumor microenvironment. Moreover, DCs + pomalidomide with dexamethasone + PD-L1 blockade induced the activation of cell-mediated immunity by increasing Th1-specific immune responses, as evidenced by the increased production of IFN-γ and a decrease in the regulatory-specific immune response, as evidenced by the decreased production of TGF-β, IL-10 and VEGF in the spleen and tumor microenvironment. These findings show that inducing the systemic immune response represent a means of treating myeloma. Immunotherapy clearly represents a revolution in cancer care, and promising responses have been shown to various treatments, particularly immune checkpoint inhibitors, IMiDs, DCs and CAR T cells. However, not all patients are responsive to current immunotherapies, and among those patients who do respond, the effects are not always long-lasting. Thus, combination approaches are a cornerstone of cancer therapy for improving patient outcomes in MM. This study demonstrated that the combination of DC vaccination + pomalidomide with dexamethasone + PD-L1 blockade synergistically enhances myeloma immune responses to inhibit tumor growth, restores and enhances host immune effector cells, and reduces the generation of immune suppressor cells in MM. This study provides a framework for developing and understanding the role of immunotherapeutic modalities employing DCs, pomalidomide and PD-L1 blockade to inhibit tumor growth and restore immune function in myeloma-bearing mice. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Myeloid-Specific SHP-2 Ablation Induces Robust Anti-Tumor Immunity That Is Not Further Enhanced By PD-1 Blockade

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Anthos Christofides ◽  
Natalia M Tijaro-Ovalle ◽  
Halil-Ibrahim Aksoylar ◽  
Rinku Pal ◽  
Abdelrahman AA Mahmoud ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Tumor Bearing ◽  
Suppressor Function ◽  
Emergency Myelopoiesis ◽  
Myeloid Progenitors

PD-1 is a T cell inhibitor for which blocking agents have achieved success as anti-cancer therapeutics. The current view is that cancer limits host immune responses by upregulating PD-L1 in the tumor microenvironment thereby causing PD-1 ligation and inactivation of CD8+ Teff cells. Recently, we determined that PD-1 alters the differentiation of myeloid progenitors during cancer-mediated emergency myelopoiesis. We found that PD-1 is expressed in granulocyte/macrophage progenitors (GMP), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSC) that promote tumor growth. In tumor-bearing mice with myeloid-specific PD-1 ablation, accumulation of GMP and MDSC was prevented, while output of effector myeloid cells was increased. PD-1-mediated T cell inactivation is attributed to the function of SHP-2 phosphatase, which is activated by recruitment to PD-1 cytoplasmic tail. Temporal activation of SHP-2 is critical for myeloid cell fate. Activating SHP-2 mutations prevent myeloid cell differentiation and lead to the accumulation of immature myelocytes and development of leukemia. To determine whether PD-1-mediated inhibition of anti-tumor immunity relies on SHP-2-mediated effects in T cells or myeloid cells, we generated mice with conditional targeting of the Ptpn11 gene (encoding for Shp-2) and selectively eliminated Shp-2 in T cells (Shp-2fl/flLckCre) or myeloid cells (Shp-2fl/flLysMCre). No significant difference in tumor growth was observed between control Shp2fl/fl and Shp-2fl/flLckCre mice bearing B16-F10 melanoma. Strikingly, Shp-2fl/flLysMCre mice had significantly diminished tumor growth that was not further decreased by anti-PD-1 antibody, in contrast to control Shp-2fl/fl mice in which anti-PD-1 treatment significantly reduced tumor size. To determine how Shp-2 ablation affected the properties of myeloid cells, we examined CD11b+Ly6ChiLy6G- monocytic (M-MDSC), CD11b+Ly6CloLy6G+ polymorphonuclear (PMN-MDSC), CD11b+F4/80+ tumor-associated macrophages (TAM) and CD11c+MHCII+ dendritic cells (DC). No quantitative differences were observed in these myeloid subsets in tumor bearing mice among the different groups. However, M-MDSC from Shp-2fl/flLysMCre mice had elevated expression of CD86 and IFNγ, consistent with effector differentiation. Suppression assays, by measuring antigen-specific responses of OTI transgenic T cells, showed significantly attenuated suppressor function of MDSC isolated from tumor-bearing Shp-2f/fLysMCre mice compared to control or Shp-2f/fLckCre mice. CD38 is a key mediator of MDSC-mediated immunosuppression. It is an ADP-ribosyl cyclase that has ectoenzyme and receptor functions, is induced early during differentiation of myeloid progenitors by retinoic acid receptor alpha (RARα) signaling, and mediates T cell immunosuppression. Because Shp-2 is involved in the differentiation of myeloid progenitors, we examined CD38 expression. We found that expression of CD38 was significantly reduced in MDSC from Shp-2fl/flLysMCre mice compared to control and Shp-2fl/flLckCre-tumor bearing mice. Since the suppressive potency of MDSC is decreased by autophagy, and SHP-2 has been implicated in regulating autophagy in cancer cells, we examined autophagy of MDSC in our system. Assessment of autophagy in ex vivo isolated MDSC, using Cyto-ID that stains the autophagosome membrane and indicates autophagic activity, showed enhanced autophagy in MDSC isolated from tumor bearing Shp-2fl/flLysMCre mice compared to control or Shp-2fl/flLckCre mice. Enhanced autophagy was also detected in bone marrow-derived MDSC from Shp-2fl/flLysMCre mice as determined by accumulation of LC3B-II and p62 during culture under conditions of starvation-induced stress. Consistent with the diminished MDSC suppressor function, myeloid cell-specific Shp-2 ablation in tumor-bearing mice induced an increase of CD8+ T cells showing an effector phenotype with improved functionality, despite preserved expression of PD-1 and Shp-2. Together these results indicate that inhibition of PD-1-mediated SHP-2 activation in myeloid progenitors, thereby preventing the accumulation of immature immunosuppressive MDSC and promoting the differentiation of effector myeloid cells, might be a previously unidentified mechanism by which PD-1 blockade mediates anti-tumor function. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bcl6 Preserves the Suppressive Function of Regulatory T Cells during Tumorigenesis

2020 ◽  
Author(s):  
Yiding Li ◽  
Zhiming Wang ◽  
Huayu Lin ◽  
Lisha Wang ◽  
Xiangyu Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Treg Cell ◽  
Synergistic Effects ◽  
Treg Cells ◽  
Immune Checkpoint Blockade ◽  
Effector T Cells ◽  
Tumor Control ◽  
Suppressive Function

AbstractDuring tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3+ cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-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 Single-cell RNA Sequencing Reveals Immunosuppressive Myeloid Cell Diversity and Restricted Cytotoxic Effector Cell Trafficking and Activation During Malignant Progression in Glioma

2021 ◽  
Author(s):  
Sakthi Rajendran ◽  
Clayton Peterson ◽  
Alessandro Canella ◽  
Yang Hu ◽  
Amy Gross ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Malignant Progression ◽  
Low Grade ◽  
Cell Trafficking ◽  
High Grade ◽  
Single Cell Rna Sequencing

Low grade gliomas (LGG) account for about two-thirds of all glioma diagnoses in adolescents and young adults (AYA) and malignant progression of these patients leads to dismal outcomes. Recent studies have shown the importance of the dynamic tumor microenvironment in high-grade gliomas (HGG), yet its role is still poorly understood in low-grade glioma malignant progression. Here, we investigated the heterogeneity of the immune microenvironment using a platelet-derived growth factor (PDGF)-driven RCAS (replication-competent ASLV long terminal repeat with a splice acceptor) glioma model that recapitulates the malignant progression of low to high-grade glioma in humans and also provides a model system to characterize immune cell trafficking and evolution. To illuminate changes in the immune cell landscape during tumor progression, we performed single-cell RNA sequencing on immune cells isolated from animals bearing no tumor (NT), LGG and HGG, with a particular focus on the myeloid cell compartment, which is known to mediate glioma immunosuppression. LGGs demonstrated significantly increased infiltrating T cells, CD4 T cells, CD8 T cells, B cells, and natural killer cells in the tumor microenvironment, whereas HGGs significantly abrogated this infiltration. Our study identified two distinct macrophage clusters in the tumor microenvironment; one cluster appeared to be bone marrow-derived while another was defined by overexpression of Trem2, a marker of tumor associated macrophages. Our data demonstrates that these two distinct macrophage clusters show an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG which evolves to an immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG that restricts T cell recruitment and activation. We identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Interestingly, these results were mirrored by our analysis of the TCGA dataset, which demonstrated a statistically significant association between CD74 overexpression and decreased overall survival in AYA patients with grade II gliomas. Targeting immunosuppressive myeloid cells and intra-tumoral macrophages within this therapeutic window may ameliorate mechanisms associated with immunosuppression before and during malignant progression.

Sign in / Sign up

Export Citation Format

Share Document