Neutrophils: Musketeers against immunotherapy

Zahid, Kashif Rafiq; Raza, Umar; Tumbath, Soumya; Jiang, Lingxiang; Xu, Wei; Huang, Xiumei

doi:10.3389/fonc.2022.975981

Cited by 17 publications

(16 citation statements)

References 346 publications

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“…Thus, beside their role as unspecific biomarkers of an inflammatory profile, neutrophils deserve investigation to unravel the specific mechanisms driving their prognostic and predictive roles, to control them in a therapeutic perspective. Indeed, several approaches for neutrophil antagonism are under investigation to potentiate immune checkpoint blockade [ 31 ]. In human studies, neutrophils are identified as CD66b+, CD15+ CD14−, and CD33+ white blood cells.…”

Section: Discussionmentioning

confidence: 99%

Low-Baseline PD1+ Granulocytes Predict Responses to Atezolizumab–Bevacizumab in Hepatocellular Carcinoma

Giovannini

Suzzi

Tovoli

et al. 2023

Cancers

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Introduction: Immune check point inhibitors have recently entered the armamentarium of advanced hepatocellular carcinoma (HCC) treatment. Among them, the combination of atezolizumab plus bevacizumab has pushed it a step forward; however, a number of patients still present primary non-responses without any biomarker to predict responses to different options. Here, we aimed to identify a putative baseline biomarker to predict the response to atezolizumab–bevacizumab, by investigating whether baseline PD1+ and PD-L1+ peripheral granulocyte percentages might offer a non-invasive, cheap, and easily feasible assay. Methods: A prospective Italian cohort of 34 patients treated by atezolizumab–bevacizumab was tested to assay the baseline percentage of peripheral granulocytes and their PD1 and PD-L1 expression. The neutrophil to lymphocyte ratio (NLR) was also considered, and all data were compared with the clinical course of patients. Results: A low-baseline PD1+ peripheral granulocyte percentage turned out to predict responder patients (mean ±SD of PD1+ granulocyte percentage in responders versus non-responders: 9.9 ± 9.1 vs. 29.2 ± 17.6; student’s t-test, p < 0.01). In line, patients identified by a low PD1+ granulocyte percentage displayed a longer TTP (log-rank test, p < 0.0001). A lower granulocyte percentage on total white blood cells, irrespective of PD1 or PD-L1 expression, is also associated with responses to atezolizumab–bevacizumab (log-rank test, p < 0.05). No predictive value was observed for either the PD-L1+ granulocyte percentage or NLR. Conclusions: A low-baseline PD1+ peripheral granulocyte percentage is associated with responses to atezolizumab–bevacizumab treatment in advanced HCC. These findings encourage evaluating this minimally invasive, cheap, and easy test in further independent cohorts and outlining the relevance of innate immunity in the response to immune-checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 99%

Low-Baseline PD1+ Granulocytes Predict Responses to Atezolizumab–Bevacizumab in Hepatocellular Carcinoma

Giovannini

Suzzi

Tovoli

et al. 2023

Cancers

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“… 32 Much attention has been paid to the role of neutrophils in tumor immunity. 11 , 33 Some studies showing that neutrophils and granulocyte colony-stimulating factor promote tumor development 34 , 35 and others pointing out that the effector function of neutrophils is related to antitumor immune suppression. 11 , 36 Recent studies have found that the neutrophil precursors PMN-MDSCs are vulnerable to ferroptosis which promotes the suppression of tumor immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…There is currently no evidence linking IGFBP1 with ferroptosis in lung cancer cells, but early studies have shown that IGFBP1 protein can be efficiently cleaved by enzymes secreted by immune cells, such as central granulocyte-derived proteases cathepsin G and elastase, in vitro and in vivo. 34 Tumor hypoxia and inflammatory infiltration provide strong support for the aggregation and activation of central granulocytes. 38 Our preliminary study also showed that LUAD is associated with the infiltration of PMN-MDSCs with ferroptosis fragility.…”

Section: Discussionmentioning

confidence: 99%

Clinical Characterization of the Expression of Insulin-Like Growth Factor Binding Protein 1 and Tumor Immunosuppression Caused by Ferroptosis of Neutrophils in Non-Small Cell Lung Cancer

Wang¹,

Xing²,

Deng³

et al. 2023

IJGM

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Purpose The efficacy of immunotherapy for non-small cell lung cancer (NSCLC) is limited owing to cold tumors and drug resistance. Therefore, it is important to identify the molecular mechanisms underlying immune evasion in NSCLC. Spontaneous ferroptosis of neutrophils has been suggested as a key mechanism of immunosuppression in cancer. Insulin-like growth factor binding protein 1 (IGFBP1) plays an important role in immune infiltration in several cancers. However, the role of IGFBP1 in NSCLC is unknown. Therefore, in this study, we aimed to investigate the association of IGFBP1 mRNA expression with infiltration of myeloid-derived suppressor cells and prognosis in NSCLC. Patients and Methods Retrospective RNA-seq data from 990 patients in the Cancer Genome Atlas (TCGA) database were analyzed in relation to patient clinical characteristics. The Timer2 database was used to assess immune infiltration, and the FerrDb V2 database was used to obtain ferroptosis-related genes. Finally, the results were validated by the proteomic analysis of serum samples collected from six patients with NSCLC and six healthy individuals. Results IGFBP1 expression was enriched in lung adenocarcinoma samples and positively correlated with the pathological grade of NSCLC. IGFBP1 expression was an independent prognostic factor for the overall survival of patients with NSCLC. In addition, IGFBP1 expression correlated with myeloid-derived suppressor cell infiltration. Notably, Gene Ontology analysis of IGFBP1 -related genes revealed that the major molecular functions of their protein products were related to NADP + 1-oxidoreductase activity. Furthermore, expression levels of multiple ferroptosis suppressor genes positively correlated with IGFBP1 expression. Conclusion High IGFBP1 expression indicates a poor prognosis in patients with NSCLC, which may be related to tumor immunosuppression caused by neutrophil ferroptosis.

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“…The mature neutrophil population MMP9, expressing immunosuppressive markers showed higher frequency in the control group and therapeutic vaccine alone group compared to the mice that received the sequential treatment. These neutrophils have been stated to have potent immunosuppressive capabilities in oncology (37). The same might be true in the context of chronic infection, where it has been described that HBV may reduce neutrophil responses (38).…”

Section: Discussionmentioning

confidence: 99%

Sustained liver HBsAg loss and clonal T and B cell expansion upon therapeutic DNA vaccination require low HBsAg levels

Conceição-Neto,

Pierson,

Vacca

et al. 2023

Preprint

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Background & AimsSuppression of HBV DNA, inhibition of HBsAg production and therapeutic vaccination to reverse HBV-specific T-cell exhaustion in chronic HBV patients are likely required to achieve functional cure. In the AAV-HBV mouse model, therapeutic vaccination can be effective in clearing HBsAg when hepatitis B surface (HBsAg) levels are low. The factor(s) required for mounting an effective immune control of HBV infection are unclear. Using a single-cell approach, we investigated the liver immune environment in the context of different levels of HBsAg as well as upon sustained HBsAg loss through treatment with an HBV specific GalNAc-siRNA followed by therapeutic vaccination.MethodsC57BL/6 mice were transduced with a range of rAAV-HBV DNA to express different HBsAg levels. Mice were treated with GalNAc-siRNA targeting HBV transcripts to lower the HBsAg levels and then vaccinated 4 times with a DNA vaccine encoding HBV Core, Pol and Surface. We used single-cell RNA-sequencing on homogenised liver resident cells, paired with single-cell V(D)J receptor sequencing to understand the changes in the liver immune microenvironment.ResultsTreatment with GalNAc-HBV siRNA followed by therapeutic vaccination, achieved a sustained HBsAg loss in all mice. This was accompanied by an induction of CD4 follicular helper T-cell responses, polyclonal activation of CD8 T-cells in the liver and clonal expansion of plasma cells that were responsible for antibody production.ConclusionsThis study provides novel insight into the immune changes in the liver at the single-cell level, highlighting the correlation between the induced reduction in HBsAg levels and the clonal expansion of CD4 follicular helper T-cells, CD8 cytotoxic T-cells, plasma cells, and ISG-producing neutrophils in the liver upon HBV siRNA and subsequent therapeutic vaccine treatment.Lay SummaryChronic hepatitis B infection is characterized by a complex interplay between immune responses and viral replication in the liver. To achieve functional cure a combination of different treatments is likely required. In this study single-cell approach was used to understand the liver microenvironment in the context of different HBsAg levels followed by therapeutic vaccination in AAV-HBV mouse model and to identify key factors required to achieve functional cure.Graphical abstractHighlightsAAV-HBV transduced mice sequentially treated with GalNAc-siRNA and therapeutic vaccine showed sustained HBsAg loss.The sustained HBsAg loss correlates with increased proportion and clonal expansion of CD4 follicular helper T-cells, CD8 cytotoxic T-cells, plasma cells, and ISG producing neutrophils in the liver.Baseline levels of HBsAg are important to determine outcome of therapeutic vaccination in mice.

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Neutrophils: Musketeers against immunotherapy

Cited by 17 publications

References 346 publications

Low-Baseline PD1+ Granulocytes Predict Responses to Atezolizumab–Bevacizumab in Hepatocellular Carcinoma

Low-Baseline PD1+ Granulocytes Predict Responses to Atezolizumab–Bevacizumab in Hepatocellular Carcinoma

Clinical Characterization of the Expression of Insulin-Like Growth Factor Binding Protein 1 and Tumor Immunosuppression Caused by Ferroptosis of Neutrophils in Non-Small Cell Lung Cancer

Sustained liver HBsAg loss and clonal T and B cell expansion upon therapeutic DNA vaccination require low HBsAg levels

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