Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression

Fleming, Viktor; Hu, Xiaoying; Weber, Rebekka; Nagibin, Vasyl S.; Groth, Christopher; Altevogt, Peter; Utikal, Jochen; Umansky, Viktor

doi:10.3389/fimmu.2018.00398

Cited by 379 publications

(326 citation statements)

References 111 publications

(137 reference statements)

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“…39 Further, the MDSC depletion and reversal of immunosuppression correlate with increased adaptive antitumor immune responses and mproved therapeutic outcome of melanoma. 60 LCP-GMP elicited strong CTL responses, as indicated by the increased productions of pro-inflammatory cytokines IFN-γ and TNF-α by CD8 + T cells, which contributes to the inhibition of tumor progression. Though free Gem depleted MDSCs as well as partially decreased the PD-L1 expression and Tregs in tumors, it failed to improve the CD8 + T-cell effector function, and only caused a partial effect on tumor growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine nanoparticles promote antitumor immunity against melanoma

et al. 2019

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Myeloid-derived suppressor cells (MDSCs) promote tumor-mediated immunosuppression and cancer progression. Gemcitabine (Gem) is a MDSC-depleting chemotherapeutic agent; however, its clinical use is hampered by its drug resistance and inefficient in vivo delivery. Here we describe a strategy to formulate a Gem analogue gemcitabine monophosphate (GMP) into a lipid-coated calcium phosphate (LCP) nanoparticle, and investigate its antitumor immunity and therapeutic effects after systemic administrations. In the syngeneic mouse model of B16F10 melanoma, compared with free Gem, the LCP-formulated GMP (LCP-GMP) significantly induced apoptosis and reduced immunosuppression in the tumor microenvironment (TME). LCP-GMP effectively depleted MDSCs and regulatory T cells, and skewed macrophage polarization towards the antitumor M1 phenotype in the TME, leading to enhanced CD8+ T-cell immune response and profound tumor growth inhibition. Thus, engineering the in vivo delivery of MDSC-depleting agents using nanotechnology could substantially modulate immunosuppressive TME and boost T-cell immune response for enhanced antitumor efficacy.

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Section: Discussionmentioning

confidence: 99%

Gemcitabine nanoparticles promote antitumor immunity against melanoma

et al. 2019

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“…In addition, we observed an increase in CD11b High Gr-1 low cells (MDSC-like populations) in the spleen of dasatinib-treated mice. This population may be related to tumor progression since MDSCs have been reported as immunosuppressive functions to promote tumor progress 40,41 . Further, CD11b + Gr-1 − (monocyte populations) were also increased in the spleen of dasatinib-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Dasatinib exacerbates splenomegaly of mice inoculated with Epstein-Barr virus-infected lymphoblastoid cell lines

Kotaki

Kawashima

Yamamoto

et al. 2020

Sci Rep

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Latent infection of epstein-Barr virus (eBV) is associated with a poor prognosis in patients with B cellmalignancy. We examined whether dasatinib, a multi kinase inhibitor, which is broadly used for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia is effective on EBV-positive B cell malignancies, using lymphoblastoid cell lines (LCLs) in vitro and in vivo. As a result, in vitro experiments showed that dasatinib induced cell death of the eBV-LcLs which was not accompanied with a lytic reactivation of EBVs. To evaluate the effectiveness in EBV latency type III represented by immunodeficiency lymphoma, LCL-inoculated immunodeficient NOD/shi-scid/Il2rg nul (NOG) mice were treated with dasatinib. However, in vivo experiments revealed that dasatinib treatment exacerbated tumor cell infiltration into the spleen of LCL-inoculated NOG mice, whereas tumor size at the inoculated site was not affected by the treatment. These results suggest that dasatinib exacerbates the pathogenesis at least in some situations although the drug is effective in vitro. Hence, we should carefully examine a possibility of dasatinib repositioning for eBV + B cell malignancies.Epstein-Barr virus (EBV) is a human oncogenic herpesvirus which persistently infects more than 90% of the healthy adult humans 1,2 . While primary EBV infection in adolescents causes infectious mononucleosis, the infection in childhood is usually asymptomatic. After the primary infection, EBV establishes a lifelong persistent infection preferentially in resting memory B cells 3-5 . Although the persistent EBV infection is usually asymptomatic, EBV may be involved in various B cell malignancies, such as diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, classical Hodgkin lymphoma, and post-transplant lymphoproliferative disorder.Several studies have reported that EBV is associated with a poor prognosis in patients with classical Hodgkin lymphoma and DLBCL, typically in an aged population 6-9 . Malignant EBV + B cells express several genes encoded in the EBV genome, including latent membrane proteins (LMPs) and EBV nuclear antigens (EBNAs) 2 . Based on expression profiles of the EBV-derived molecules, EBV + B cell malignancies are classified into three types of latency, latency I, II, and III. A small-scaled study in our institute suggested that patients with latency III EBV + DLBCL had a very poor prognosis, namely they died within one year from diagnosis, even though they were treated with R-CHOP, a standard therapy for DLBCL 9 . Latency III EBV + cells express most EBV-derived genes among the three types. Hence, the EBV-derived factors may be involved in the poor prognosis of the patients with latency III EBV + DLBCL. One possible therapeutic target for latency III EBV + B cell malignancies is signal transduction pathways from LMPs. LMPs, including LMP1 and LMP2A, which mimic signal transduction from

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“…In fact, targeting MDSCs 34;35 and boosting the immune system 32 have been shown to favour bacterial reduction but nonetheless failed to induce sterilizing immunity in chronically infected individuals. However, although MDSC-depletion seems to be beneficial in diseases such as cancer 36;37 , in bacterial infections such treatment would simultaneously deplete important monocytes and by extension, dendritic cells and macrophages 38 .…”

Section: Discussionmentioning

confidence: 99%

ChronicStaphylococcus aureusinfection is cured by theory-driven therapy

Zhao

Khailaie

et al. 2020

Preprint

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19Staphylococcus aureus (S. aureus) is a challenging human pathogen due to its ability to evade the 20 immune system and resist multidrug antibiotics. These evasive strategies lead to chronic and re-21 current infections. Many studies have documented that during chronic infections Myeloid Derived 22 Suppressor Cells (MDSCs) exert immunosuppressive mechanisms on T cells. A mathematical 23 model explains how the steady state of chronic infection can be disturbed and suggests therapeutic 24 strategies to clear the infection. Model-driven suggestions were tested experimentally and con-25 firmed complete clearance of S. aureus chronic infection. 26 Keywords 27 Myeloid Derived Suppressor Cells, MDSCs, Staphylococcus aureus, chronic infection, mathematical model, 28 therapy, cure, heat-killed cells 29Staphylococcus aureus (S. aureus) is a bacterial human pathogen colonizing 20%-30% of the world pop-30 ulation and responsible for the genesis of nosocomial-acquired and community-acquired bacterial infections. 31 Colonization by S. aureus is typically asymptomatical, implying an equilibrated state between host and bac-32 terium. However, the bacterium can become opportunistic often post-surgery or after implantation of medical 33 devices and can cause skin and soft tissue infections, such as dermatitis, impetigo, and cellulitis 1 , as well as 34 life-threatening conditions like pneumonia and chronic osteomyelitis 2 . Additionally, individuals with immune 35 deficiencies are more susceptible to S. aureus infections. The pathogen constitutes a serious problem in clin-36 ics worldwide because it uses multiple mechanisms to persist in the host. These include strategies of bacterial 37 1 evasion, multi-drug antibiotic resistance, immunosuppression 3 or manipulation of the host's immune regulatory 38 mechanisms, 4;5 which lead to chronic and difficult-to-treat infections. 39Typically, immunosuppression is achieved via regulatory T cells (Tregs), T cell lysis, regulatory B cells 40 (Bregs) 6 , and Myeloid-Derived Suppressor Cells (MDSCs). In the case of S. aureus chronic infections, immuno-41 suppression is not attributed to Bregs, tolerogenic dendritic cells, nor Tregs 7 . Treg-depletion has only a minor 42 effect, whereas T-cell proliferation remains inhibited despite the absence of B220 + and CD11c + cells 7 . Never-43 theless, T-cell suppression in chronically infected mice has been associated with the expansion of monocytic-like 44 (CD11b + Ly6C + Ly6G low phenotype), neutrophilic-like (CD11b + Ly6C low Ly6G + phenotype) and eosonophilic-45 like (CD11b + Ly6C low Ly6G low phenotype) MDSCs 7;8;9;10;11 , affirming the dominant immunosuppressive role of 46 MDSCs during chronic S. aureus infections. 47MDSCs constitute a heterogeneous population of immature myeloid cells, which exert their suppressive 48 effect on T cells by producing reactive oxygen species, nitric oxide, arginase, and inducible nitric oxide syn-49 thase. Significant MDSC expansion and the consequent immunosuppressive effect were reported in long-lasting 50 p...

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Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression

Cited by 379 publications

References 111 publications

Gemcitabine nanoparticles promote antitumor immunity against melanoma

Gemcitabine nanoparticles promote antitumor immunity against melanoma

Dasatinib exacerbates splenomegaly of mice inoculated with Epstein-Barr virus-infected lymphoblastoid cell lines

ChronicStaphylococcus aureusinfection is cured by theory-driven therapy

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