CD4+CD25hiCD127− Treg and CD4+CD45R0+CD49b+LAG3+ Tr1 cells in bone marrow and peripheral blood samples from children with neuroblastoma

Morandi, Fabio; Pozzi, Sarah; Cangemi, Giuliana; Amoroso, Loredana; Carlini, Barbara; Pistoia, Vito; Corrias, Maria Valeria

doi:10.1080/2162402x.2016.1249553

Cited by 19 publications

(16 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, anti-CD4 mAb treatment showed activity in CD4 + T cell lymphomas, without significantly increasing the risk of life-threatening infections 42 , 43 . However, the role of CD4 + immune regulatory T cell subsets is still debated in NB patients and controversial data on the potential role of Treg have been reported 44 – 46 , while CD4 + LAG-3 + Tr1 cells seemed reduced 46 . Finally, further studies in pre-clinical models should be considered to confirm the possible efficacy of this novel therapeutic strategy before clinical testing in patients with refractory or relapsing NB.…”

Section: Discussionmentioning

confidence: 99%

Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma

Rigo

Emionite

Daga

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Anti-PD-1 or anti-PD-L1 blocking monoclonal antibodies (mAbs) have shown potent anti-tumor effects in adult cancer patients and clinical studies have recently been started in pediatric cancers, including high-risk/relapsing neuroblastoma (NB). Therefore, we studied the effects of anti-PD-1/PD-L1 mAbs in two syngeneic models of disseminated NB generated by the injection of either Neuro2a or NXS2 cells, which express PD-L1. In addition, we tested the combination of these agents with the immuneenhancing cytokine IL-21, the Ecto-NTPDase inhibitor POM-1, an anti-CD25 mAb targeting Treg cells, or an anti-CD4 mAb. We previously showed that CD4-transient depletion removes CD4 + CD25 + Treg cells and other CD4 + CD25 − regulatory subsets. Here we show that mono-therapy with anti-PD-1/PD-L1 mAbs had no effect on systemic NB progression in vivo, and also their combination with IL-21, POM-1 or anti-CD25 mAb was ineffective. The combined use of anti-PD-1 with an anti-CD4 mAb mediated a very potent, CD8-dependent, synergistic effect leading to significant elongation of tumor-free survival of mice, complete tumor regression and durable anti-NB immunity. Similar results were obtained by combining the anti-PD-L1 and anti-CD4 mAbs. These findings indicate that both PD-1/PD-L1 and CD4 + T cell-related immune-regulatory mechanisms must be simultaneously blocked to mediate therapeutic effects in these models.Immune checkpoints are fundamental for the physiological maintenance of tolerance and protection of tissues from the damage that an unregulated immune response may cause. It is now clear that immune checkpoint dysregulation represents an important mechanism through which tumors escape immune system recognition and progress 1 . Studies in preclinical tumor models and cancer patients have proven that the targeting of immune checkpoints restores a silenced anti-tumor immune response, which then becomes effective in eliminating tumor cells. Indeed, the monoclonal antibodies (mAbs) blocking immune checkpoints such as Cytotoxic T-Lymphocyte Antigen (CTLA)-4 and Programed Death-Ligand1 (PD-L1)/Programed Death-1 (PD-1) showed extraordinary anti-tumor effects in clinical trials leading to their approval as anti-cancer drugs in different metastatic cancers 2 . In particular, anti-PD-1 mAbs have shown unprecedented clinical activity in patients with metastatic melanoma 3-8 , non-small-cell lung carcinoma (NSCLC) 9,10 and renal cell carcinoma 11 , with a significant fraction of patients showing prolonged clinical benefit. The combination of anti-PD-1 and anti-CTLA-4 leads to a further increase in clinical responses in metastatic melanoma 12 . Synergistic therapeutic activity may relate to the different site of action of CTLA4 and PD-L1/PD-1-blocking agents, i.e. the secondary lymphoid organs and the peripheral tissues, respectively. In addition, CTLA-4 blockade induces a proliferative gene expression signature

show abstract

Section: Discussionmentioning

confidence: 99%

Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma

Rigo

Emionite

Daga

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Some studies have shown an increased number of circulating Treg cells in patients with neuroblastoma compared to healthy individuals, but was not prognostic of outcomes ( 86 , 87 ). In another report, lower frequency of Treg cells has been observed in the bone marrow and peripheral blood samples of patients with neuroblastoma compared to healthy controls ( 88 ). Interestingly, a higher proportion of Treg cells in the bone marrow and peripheral blood correlated with MYCN amplification ( 88 ).…”

Section: Tumor Microenvironment Of Neuroblastomamentioning

confidence: 93%

“…In another report, lower frequency of Treg cells has been observed in the bone marrow and peripheral blood samples of patients with neuroblastoma compared to healthy controls ( 88 ). Interestingly, a higher proportion of Treg cells in the bone marrow and peripheral blood correlated with MYCN amplification ( 88 ).…”

Section: Tumor Microenvironment Of Neuroblastomamentioning

confidence: 93%

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

Liu

Joshi

2020

Front. Immunol.

View full text Add to dashboard Cite

Neuroblastoma is the most common extracranial pediatric tumor and often presents with metastatic disease, and patients with high-risk neuroblastoma have survival rates of ~50%. Neuroblastoma tumorigenesis is associated with the infiltration of various types of immune cells, including myeloid derived suppressor cells, tumor associated macrophages (TAMs), and regulatory T cells, which foster tumor growth and harbor immunosuppressive functions. In particular, TAMs predict poor clinical outcomes in neuroblastoma, and among these immune cells, TAMs with an M2 phenotype comprise an immune cell population that promotes tumor metastasis, contributes to immunosuppression, and leads to failure of radiation or checkpoint inhibitor therapy. This review article summarizes the role of macrophages in tumor angiogenesis, metastasis, and immunosuppression in neuroblastoma and discusses the recent advances in “macrophage-targeting strategies” in neuroblastoma with a focus on three aspects: (1) inhibition of macrophage recruitment, (2) targeting macrophage survival, and (3) reprogramming of macrophages into an immunostimulatory phenotype.

show abstract

“…Morandi and colleagues found that Treg (CD4+CD25hiCD127−) and Tr1 (CD4+CD45R0+CD49b+LAG3+) subsets are decreased in NBL patients compared to controls, but no correlation was found with prognostic factors, such as age and stage. MYCN amplification was the only prognostic factor associated with higher levels of Treg numbers in BM and Tr1 levels in PB [41]. In addition, CD4+ and CD8+ T cells show increased surface expression levels of the checkpoint inhibitor CTLA-4, and PD-1 on CD4 T cells.…”

Section: Immune Cells In Peripheral Bloodmentioning

confidence: 95%

Monitoring Immune Responses in Neuroblastoma Patients during Therapy

Szanto

Cornel

Vijver

et al. 2020

Cancers

View full text Add to dashboard Cite

Neuroblastoma (NBL) is the most common extracranial solid tumor in childhood. Despite intense treatment, children with this high-risk disease have a poor prognosis. Immunotherapy showed a significant improvement in event-free survival in high-risk NBL patients receiving chimeric anti-GD2 in combination with cytokines and isotretinoin after myeloablative consolidation therapy. However, response to immunotherapy varies widely, and often therapy is stopped due to severe toxicities. Objective markers that help to predict which patients will respond or develop toxicity to a certain treatment are lacking. Immunotherapy guided via immune monitoring protocols will help to identify responders as early as possible, to decipher the immune response at play, and to adjust or develop new treatment strategies. In this review, we summarize recent studies investigating frequency and phenotype of immune cells in NBL patients prior and during current treatment protocols and highlight how these findings are related to clinical outcome. In addition, we discuss potential targets to improve immunogenicity and strategies that may help to improve therapy efficacy. We conclude that immune monitoring during therapy of NBL patients is essential to identify predictive biomarkers to guide patients towards effective treatment, with limited toxicities and optimal quality of life.

show abstract

CD4⁺CD25^hiCD127⁻ Treg and CD4⁺CD45R0⁺CD49b⁺LAG3⁺ Tr1 cells in bone marrow and peripheral blood samples from children with neuroblastoma

Cited by 19 publications

References 24 publications

Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma

Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

Monitoring Immune Responses in Neuroblastoma Patients during Therapy

Contact Info

Product

Resources

About