Polymorphonuclear myeloid-derived suppressor cells limit antigen cross-presentation by dendritic cells in cancer

Ugolini, Alessio; Tyurin, Vladimir A.; Tyurina, Yulia Y.; Tcyganov, Evgenii N.; Donthireddy, Laxminarasimha; Kagan, Valerian E.; Gabrilovich, Dmitry I.; Veglia, Filippo

doi:10.1172/jci.insight.138581

Cited by 98 publications

(76 citation statements)

References 33 publications

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“…The CD8 + T cell/Treg ratio in the tumor decreased compared with healthy PBMCs, suggesting that Tregs participate to the immunosuppressive environment of GCT. MDSCs are a heterogeneous cell population characterized by the ability to suppress T cells and NK cell function ( 40 ), as well as the ability to limit DC cross-presentation ( 41 ). Two studies in RCC ( 42 ) and colorectal cancer ( 43 ) found intratumor MDSCs to amount at about 5% and 2.99% of total tumor cell suspension, respectively.…”

Section: Discussionmentioning

confidence: 99%

Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target

Pierini¹,

Tanyi²,

Simpkins³

et al. 2020

JCI Insight

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Granulosa cell tumors (GCT) are rare ovarian malignancies. Due to the lack of effective treatment in late relapse, there is a clear unmet need for novel therapies. Forkhead Box L2 (FOXL2) is a protein mainly expressed in granulosa cells (GC) and therefore is a rational therapeutic target. Since we identified tumor infiltrating lymphocytes (TILs) as the main immune population within GCT, TILs from 11 GCT patients were expanded, and their phenotypes were interrogated to determine that T cells acquired late antigen-experienced phenotypes and lower levels of PD1 expression. Importantly, TILs maintained their functionality after ex vivo expansion as they vigorously reacted against autologous tumors (100% of patients) and against FOXL2 peptides (57.1% of patients). To validate the relevance of FOXL2 as a target for immune therapy, we developed a plasmid DNA vaccine (FoxL2–tetanus toxin; FoxL2-TT) by fusing Foxl2 cDNA with the immune-enhancing domain of TT. Mice immunization with FoxL2-TT controlled growth of FOXL2-expressing ovarian (BR5) and breast (4T1) cancers in a T cell–mediated manner. Combination of anti–PD-L1 with FoxL2-TT vaccination further reduced tumor progression and improved mouse survival without affecting the female reproductive system and pregnancy. Together, our results suggest that FOXL2 immune targeting can produce substantial long-term clinical benefits. Our study can serve as a foundation for trials testing immunotherapeutic approaches in patients with ovarian GCT.

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Section: Discussionmentioning

confidence: 99%

Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target

Pierini¹,

Tanyi²,

Simpkins³

et al. 2020

JCI Insight

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“…Numerous mechanisms by which MDSCs inhibit immune responses have been reported, including inhibition of the antitumor activity of cytotoxic T cells [ 89 ], suppression of NK cell [ 90 ], macrophage and dendritic cell function [ 91 ], and induction of Tregs and Bregs [ 92 , 93 ]. ARG1, nitric oxide (NO), and PGE2 [ 94 ] are major contributors to MDSCs’ immune suppressive activity [ 88 ].…”

Section: Myeloid Derived Suppressor Cells (Mdscs) In Gbmmentioning

confidence: 99%

“…The cDC1s have a pivotal role in antitumor immunity and in the success of immunotherapy [ 91 , 147 , 148 , 149 , 150 , 151 ]. However, the specific role of cDCs in the setting of GBM has yet to be elucidated.…”

Section: Dendritic Cells In Gbmmentioning

confidence: 99%

“…Tumor-derived factors and metabolites produced by other immune cells also affected the functionality of cDCs in cancer. For example, the accumulation of MDSC-derived oxidized lipids in cDC1s was implicated in the negative regulation of their ability to cross-present tumor antigens [ 91 , 147 ]. In GBM, fibrinogen-like Protein 2 (FGL2), produced by tumor cells, interfered with GM-CSF signaling, blunting the differentiation of CD103+ cDC1s and consequently, lowering the CD8+ T-cell response [ 155 ].…”

Section: Dendritic Cells In Gbmmentioning

confidence: 99%

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Myeloid Cells in Glioblastoma Microenvironment

Leo

Ugolini

Veglia

2020

Cells

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102

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Glioblastoma (GBM) is the most aggressive, malignant primary brain tumor in adults. GBM is notoriously resistant to immunotherapy mainly due to its unique immune microenvironment. High dimensional data analysis reveals the extensive heterogeneity of immune components making up the GBM microenvironment. Myeloid cells are the most predominant contributors to the GBM microenvironment; these cells are critical regulators of immune and therapeutic responses to GBM. Here, we will review the most recent advances on the characteristics and functions of different populations of myeloid cells in GBM, including bone marrow-derived macrophages, microglia, myeloid-derived suppressor cells, dendritic cells, and neutrophils. Epigenetic, metabolic, and phenotypic peculiarities of microglia and bone marrow-derived macrophages will also be assessed. The final goal of this review will be to provide new insights into novel therapeutic approaches for specific targeting of myeloid cells to improve the efficacy of current treatments in GBM patients.

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“…As the two main components, TIICs and stromal cells are regarded as valuable for the effect of tumor immunotherapy [10][11][12][13][14]. It is reported that immune cells, such as T and B cells, macrophages, dendritic cells, monocytes, etc., interact with tumor cells and are correlated to tumor cell proliferation, metastasis and prognosis [15][16][17]. Regulated by Tregs and M2 macrophages, tumor-in ltrating lymphocytes (TILs) participate in the clinical course of various cancers [18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of immune-related genes and comparative analysis of immune cell infiltration in lung adenocarcinoma of different genders

Fan¹,

2020

Preprint

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Background Lung adenocarcinoma (LUAD) is one of the most important subtypes of lung cancer. Compared with male LUAD patients, female patients have a higher incidence, but better long-term survival rate, with unknown reasons. In this study, we aimed to explore the effect of gender on immune cell infiltration of LUAD tumor microenvironment (TME), and tried to clarify the reasons for the different clinical characteristics of male and female LUAD patients, by conducting a comparative analysis of the TME in female and male LUAD patients. Methods We calculated immune and stromal scores of LUAD patients samples from The Cancer Genome Atlas (TCGA) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to reveal biological processes of intersecting genes. Cox regression analysis and protein-protein interaction (PPI) network analysis were conducted to screen immune-related prognostic genes in female (CCR2, LCP2, and PTPRC) and male (BTK and CCR2) patients. Kaplan-Meier survival analysis was used to evaluate prognostic value of identified genes. Mann-Whitney test was used to compare various indicators of male patients and female patients. The main result was subsequently validated in 420 cases from GSE72094. Results 304 and 368 intersecting genes were identified in female and male patients respectively. The immune score is ranged from − 943.17 to 3229.35 among female patients with LUAD and from − 541.75 to 3441.78 among male patients with LUAD. The stromal score is ranged from − 1790.23 to 2097.27 among female patients and from − 1786.94 to 1722.70 among male patients. The immune and stromal scores of women were higher than those of men (P < 0.05). CCR2, LCP2 and PTPRC were identified as the most important immune-related prognostic genes in women. BTK and CCR2 were identified as the most important immune-related prognostic genes in men. Female patients had a higher proportion of memory B cells than that of male patients, while the percentage of T cells CD4 naïve and resting NK cells was lower in female patients (P < 0.05). Conclusions This study compared the differences in TIICs in the TME of male and female LUAD patients, and identified prognosis-related genes for patients of different genders.

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Polymorphonuclear myeloid-derived suppressor cells limit antigen cross-presentation by dendritic cells in cancer

Cited by 98 publications

References 33 publications

Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target

Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target

Myeloid Cells in Glioblastoma Microenvironment

Prognostic value of immune-related genes and comparative analysis of immune cell infiltration in lung adenocarcinoma of different genders

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