Immune checkpoint molecules in neuroblastoma: A clinical perspective

Pathania, Anup Singh; Prathipati, Philip; Murakonda, Swati P; Murakonda, Ajay B; Srivastava, Ankit; Avadhesh, None; Byrareddy, Siddappa N.; Coulter, Don W.; Gupta, Subash C.; Challagundla, Kishore B.

doi:10.1016/j.semcancer.2022.06.013

Cited by 11 publications

(6 citation statements)

References 132 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Firstly, due to a lack of individual-level records, we could not obtain specific treatment details of the patients, including the surgical techniques and chemotherapy or radiotherapy plans adopted, which restricted our further evaluation of their impact on the long-term survival of the patients. Secondly, recent studies have shown that specific molecular characteristics of neuroblastoma are associated with tumor sub-categories [38,39] and clinical outcomes [34,40]. Although we applied stratification factors to reduce data bias, cytogenetic, molecular, or unknown factors related to patients' survival were still unavoidably omitted.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Survival of Neuroblastoma Patients Receiving Surgery, Chemotherapy, and Radiotherapy: A Propensity Score Matching Study

Wang

Yang

et al. 2023

JCM

View full text Add to dashboard Cite

Neuroblastoma is the most common extracranial solid malignancy in children. This study was undertaken to determine the long-term survival of neuroblastoma patients receiving conventional therapeutics (surgery, chemotherapy, and radiotherapy). The neuroblastoma patients examined were registered in the Surveillance, Epidemiology and End Results (SEER) database (1975–2016). Using propensity score matching analysis, the patients were paired by record depending on whether they received surgery, chemotherapy, or radiotherapy. Univariate and multivariate analyses of the disease-specific survival of the paired patients were performed by the log-rank test and Cox regression assay. A total of 4568 neuroblastoma patients were included in this study. During 1975–2016, the proportion of histopathological grade III/IV cases receiving surgery gradually increased, while the number of patients with tumors of grade I to IV undergoing chemotherapy or radiotherapy was stable or even decreased. After propensity score analysis, for Grade I + II and Grade III tumors, surgery obviously improved the disease-specific survival of patients, while chemotherapy was unfavorable for patient prognosis, and radiotherapy exerted no obvious effect on the patients. However, no matter what treatment was chosen, the patients with advanced-histopathological-grade tumors had a poor prognosis. Meanwhile, for all histopathological grades, the patients receiving surgery and subsequent chemotherapy or radiotherapy suffered from worsen disease-specific survival than those simply undergoing surgery. Fortunately, the negative effects of surgery, chemotherapy, or radiotherapy improved gradually over time. Surgery improved the long-term survival of the neuroblastoma patients, while chemotherapy and radiotherapy exerted an unfavorable impact on patient outcome. These results provide an important reference for the clinical treatment of neuroblastoma.

show abstract

Section: Discussionmentioning

confidence: 99%

Long-Term Survival of Neuroblastoma Patients Receiving Surgery, Chemotherapy, and Radiotherapy: A Propensity Score Matching Study

Wang

Yang

et al. 2023

JCM

View full text Add to dashboard Cite

show abstract

“…Instead, we believe that the use of metronomic low dose of chemotherapeutics such as MTX, capable of exposing the host immune system to large amounts of tumor antigens and damage-associate molecular patterns (DAMPs), could overcome the relative coldness of childhood cancer, as high-risk NB. Therefore, this study provides a rational approach based on intra-tumoral recall of immune effector cells that allows for greater efficacy of the proposed immunotherapy [ 96 , 97 ]. Further investigation in a prospective study with a larger number of human NB samples, will be crucial to confirm therapeutic efficacy of MTP treatment.…”

Section: Discussionmentioning

confidence: 99%

Combined mitoxantrone and anti-TGFβ treatment with PD-1 blockade enhances antitumor immunity by remodelling the tumor immune landscape in neuroblastoma

Lucarini

D’Amico

Pastorino

et al. 2022

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we identified a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitize poorly T-cell-infiltrated neuroblastoma (NB) to the host antitumor immune response. Methods 975A2 and 9464D NB cell lines derived from spontaneous tumors of TH-MYCN transgenic mice were employed to study drug combinations able of enhancing the antitumor immune response using in vivo and ex vivo approaches. Migration of immune cells towards drug-treated murine-derived organotypic tumor spheroids (MDOTS) were assessed by microfluidic devices. Activation status of immune cells co-cultured with drug-treated MDOTS was evaluated by flow cytometry analysis. The effect of drug treatment on the immune content of subcutaneous or orthotopic tumors was comprehensively analyzed by flow-cytometry, immunohistochemistry and multiplex immunofluorescence. The chemokine array assay was used to detect soluble factors released into the tumor microenvironment. Patient-derived organotypic tumor spheroids (PDOTS) were generated from human NB specimens. Migration and activation status of autologous immune cells to drug-treated PDOTS were performed. Results We found that treatment with low-doses of mitoxantrone (MTX) recalled immune cells and promoted CD8+ T and NK cell activation in MDOTS when combined with TGFβ and PD-1 blockade. This combined immunotherapy strategy curbed NB growth resulting in the enrichment of a variety of both lymphoid and myeloid immune cells, especially intratumoral dendritic cells (DC) and IFNγ- and granzyme B-expressing CD8+ T cells and NK cells. A concomitant production of inflammatory chemokines involved in remodelling the tumor immune landscape was also detected. Interestingly, this treatment induced immune cell recruitment against PDOTS and activation of CD8+ T cells and NK cells. Conclusions Combined treatment with low-dose of MTX and anti-TGFβ treatment with PD-1 blockade improves antitumor immunity by remodelling the tumor immune landscape and overcoming the immunosuppressive microenvironment of aggressive NB.

show abstract

“…The immune checkpoint acts as an immune system suppressor, which prevents the body’s immune system from producing an effective anti-tumor immune response by suppressing immune cell function, hence facilitating the immune evasion of the tumor ( 37 ). Therefore, we analyzed the relationship between MINDY2 expression and immune checkpoint-related genes in PC, finding a strong and positive correlation between MINDY2 expression and PDCD1LG2, HAVCR2, CD274, TIGIT, SIGLEC15, and CTLA.…”

Section: Discussionmentioning

confidence: 99%

The deubiquitinating enzyme MINDY2 promotes pancreatic cancer proliferation and metastasis by stabilizing ACTN4 expression and activating the PI3K/AKT/mTOR signaling pathway

Liu

Zhu

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

The pathogenic mechanisms of pancreatic cancer (PC) are still not fully understood. Ubiquitination modifications have a crucial role in tumorigenesis and progression. Yet, the role of MINDY2, a member of the motif interacting with Ub-containing novel DUB family (MINDY), as a newly identified deubiquitinating enzyme, in PC is still unclear. In this study, we found that MINDY2 expression is elevated in PC tissue (clinical samples) and was associated with poor prognosis. We also found that MINDY2 is associated with pro-carcinogenic factors such as epithelial-mesenchymal transition (EMT), inflammatory response, and angiogenesis; the ROC curve suggested that MINDY2 has a high diagnostic value in PC. Immunological correlation analysis suggested that MINDY2 is deeply involved in immune cell infiltration in PC and is associated with immune checkpoint-related genes. In vivo and in vitro experiments further suggested that elevated MINDY2 promotes PC proliferation, invasive metastasis, and EMT. Meanwhile, actinin alpha 4 (ACTN4) was identified as a MINDY2-interacting protein by mass spectrometry and other experiments, and ACTN4 protein levels were significantly correlated with MINDY2 expression. The ubiquitination assay confirmed that MINDY2 stabilizes the ACTN4 protein level by deubiquitination. The pro-oncogenic effect of MINDY2 was significantly inhibited by silencing ACTN4. Bioinformatics Analysis and Western blot experiments further confirmed that MINDY2 stabilizes ACTN4 through deubiquitination and thus activates the PI3K/AKT/mTOR signaling pathway. In conclusion, we identified the oncogenic role and mechanism of MINDY2 in PC, suggesting that MINDY2 is a viable candidate gene for PC and may be a therapeutic target and critical prognostic indicator.

show abstract

Immune checkpoint molecules in neuroblastoma: A clinical perspective

Cited by 11 publications

References 132 publications

Long-Term Survival of Neuroblastoma Patients Receiving Surgery, Chemotherapy, and Radiotherapy: A Propensity Score Matching Study

Long-Term Survival of Neuroblastoma Patients Receiving Surgery, Chemotherapy, and Radiotherapy: A Propensity Score Matching Study

Combined mitoxantrone and anti-TGFβ treatment with PD-1 blockade enhances antitumor immunity by remodelling the tumor immune landscape in neuroblastoma

The deubiquitinating enzyme MINDY2 promotes pancreatic cancer proliferation and metastasis by stabilizing ACTN4 expression and activating the PI3K/AKT/mTOR signaling pathway

Contact Info

Product

Resources

About