Dataset Information

Effect of radiochemotherapy on peripheral immune response in glioblastoma.

ABSTRACT:

Background

Glioblastoma (GBM) is a primary brain tumor with a dismal prognosis, often resistant to immunotherapy and associated with immune suppression. This study aimed to assess the impact of steroids and Stupp-regimen treatment on peripheral blood immune parameters in GBM patients and their association with outcomes.

Methods

Using cytometry panels and bioplex assays, we analyzed the immune phenotype and serum cytokines of 54 GBM patients and 21 healthy volunteers.

Results

GBM patients exhibited decreased lymphoid cell numbers (CD4, CD8 T cells, NKT cells) with heightened immune checkpoint expression and increased myeloid cell numbers (especially neutrophils), along with elevated pro-inflammatory cytokine levels. Steroid use decreased T and NK cell numbers, while radio-chemotherapy led to decreased lymphoid cell numbers, increased myeloid cell numbers, and heightened immune checkpoint expression. Certain immune cell subsets were identified as potential outcome predictors.

Conclusion

Overall, these findings shed light on the peripheral immune landscape in GBM, emphasizing the immunosuppressive effects of treatment. Baseline immune parameters may serve as prognostic indicators for treatment response.

SUBMITTER: Hampe L

PROVIDER: S-EPMC11098987 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

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Publications

Effect of radiochemotherapy on peripheral immune response in glioblastoma.

Hampe Léa L Daumoine Susy S Limagne Emeric E Roussot Nicolas N Borsotti François F Vincent Julie J Ilie Sylvia S Truntzer Caroline C Ghiringhelli François F Thibaudin Marion M

Cancer immunology, immunotherapy : CII 20240516 7

<h4>Background</h4>Glioblastoma (GBM) is a primary brain tumor with a dismal prognosis, often resistant to immunotherapy and associated with immune suppression. This study aimed to assess the impact of steroids and Stupp-regimen treatment on peripheral blood immune parameters in GBM patients and their association with outcomes.<h4>Methods</h4>Using cytometry panels and bioplex assays, we analyzed the immune phenotype and serum cytokines of 54 GBM patients and 21 healthy volunteers.<h4>Results</h ...[more]

PMID: 38753169

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Project description:BACKGROUND:Current standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ. METHODS:Data of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60?Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0?Gy in 30 fraction of 1.8?Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method. RESULTS:Median overall survival (OS) was 20.3?month for the entire cohort. For patients treated with NFRT median OS was 24.4?months compared to 18.5?months in patients treated with HFRT (p =?0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95% CI 1.47-3.31, p =?0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95% CI 1.21-3.13, p =?0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p =?0.504). CONCLUSIONS:Our retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.

Project description:BackgroundThe impacts of radiochemotherapy on peripheral blood cell and lymphocyte cell counts, immunoglobulin (Ig) and complement levels remain unclear. This study aims to investigate the above parameters regulated by radiotherapy (RT), induction chemotherapy (ICT) and concurrent chemotherapy (CCT) in head and neck cancer (HNC) patients.MethodsPatients with non-metastatic HNC treated by conventional intensity-modulated radiation therapy (IMRT) were enrolled in this study. Data of peripheral blood cells, lymphocyte subpopulations, complements and immunoglobulins were collected before, during and after IMRT. And conducted regular follow-up on patients. SPSS (IBM, version 26.0), R (MathSoft, 4.0.3) and Graphpad Prism were used to perform statistical analysis and plot figures.ResultsA total of 126 HNC patients undergoing RT were enrolled in this study. Among them, 44 patients received ICT, 56 patients received CCT, and 123 patients had complete survival information. Number of white blood cells (WBCs), platelets, basophils, total lymphocytes, CD4+ and CD8+ T cells, natural killer (NK) cells, B cells declined significantly during RT. Accordingly, the ratio of help T cells to suppressor T cells (Th/Ts) and the percentages of B cells, CD4+ T cells also declined. There were increased levels of neutrophils and complement 4 (C4) and percentage of NK cells during RT. ICT caused significant reductions of platelets, B cells and immunoglobulin A (IgA). CCT reduced WBCs, red blood cells (RBCs), platelets, hemoglobin (HGB), granulocytes, total lymphocytes, B cells, CD4+ and CD8+ T cells, NK cells and immunoglobulin G (IgG). Generalized linear model (GLM) analysis further confirmed that RT was a risk factor for lower total lymphocytes, B cells, CD4+ and CD8+ T cells, NK cells, Th/Ts ratios, and lower percentages of B cells, CD4+ T cells. ICT contributed to decreased Th/Ts ratios, and immunoglobulin M (IgM) and IgA levels. As for CCT, it was an unfavorable factor for reduced total lymphocytes, B cells, CD4+ and CD8+ T cells, NK cells and IgG. Conversely, complement 3 (C3) or 4 levels were higher in patients treated with RT, ICT or CCT. Importantly, we found that HNC patients with higher lymphocytes or lymphocyte percentages like CD3+, CD4+ and CD8+ T cells before or after RT had a better prognosis. While higher NK cells and NK cell percentage before RT were associated with worse prognosis. In addition, higher levels of C3 and C4 before and after RT were associated with a favorable prognosis. However, higher levels of IgA, immunoglobulin E (IgE), IgG, and IgM before RT were associated with poorer prognosis.ConclusionsTo sum up, chemoradiotherapy resulted in significant alterations in peripheral immune biomarkers which in return influenced HNC patients' survival.

Project description:Peripheral blood is an attractive source for the discovery of disease biomarkers. Gene expression profiling of whole blood or its components has been widely conducted for various diseases. However, due to population heterogeneity and the dynamic nature of gene expression, certain biomarkers discovered from blood transcriptome studies could not be replicated in independent studies. In the meantime, it's also important to know whether a reliable biomarker is shared by several diseases or specific to certain health conditions. We hypothesized that common mechanism of immune response in blood may be shared by different diseases. Under this hypothesis, we surveyed publicly available transcriptome data on infectious and autoimmune diseases derived from peripheral blood. We examined to which extent common gene dys-regulation existed in different diseases. We also investigated whether the commonly dys-regulated genes could serve as reliable biomarkers. First, we found that a limited number of genes are frequently dys-regulated in infectious and autoimmune diseases, from which we selected 10 genes co-dysregulated in viral infections and another set of 10 genes co-dysregulated in bacterial infections. In addition to its ability to distinguish viral infections from bacterial infections, these 20 genes could assist in disease classification and monitoring of treatment effect for several infectious and autoimmune diseases. In some cases, a single gene is sufficient to serve this purpose. It was interesting that dys-regulation of these 20 genes were also observed in other types of diseases including cancer and stroke where certain genes could also serve as biomarkers for diagnosis or prognosis. Furthermore, we demonstrated that this set of 20 genes could also be used in continuous monitoring of personal health. The rich information from these commonly dys-regulated genes may find its wide application in clinical practice and personal healthcare. More validation studies and in-depth investigations are warranted in the future.

Project description:Glioblastoma is a dreadful disease with very poor prognosis, median overall survival being <2 years despite standard-of-care treatment. This has led to the development of alternative strategies, among which immunotherapy is being actively tested. In particular, many clinical trials of therapeutic vaccination using peptides or tumor cells are ongoing. A major issue in implementing therapeutic vaccines in patients with high-grade glioma is that immune responses have to be elicited in the context of immunosuppressive treatments. Indeed, radiotherapy, chemotherapy, and steroids, which are part of the standard of care for patients with glioblastoma, are known to deplete leukocytes. Whether lymphopenia is beneficial or detrimental to elicitation of efficient immune responses is still debated. Here, in order to determine the impact of standard radiochemotherapy on immune cell subsets, we analyzed the phenotype and function of immune populations in 25 patients with high-grade glioma along concomitant radiochemotherapy and adjuvant chemotherapy with temozolomide. Thirteen healthy individuals were studied along the same period. We show that absolute T and B cell counts are reduced upon concomitant radiochemotherapy. Importantly, T cell counts were not restored long-term after discontinuation of treatment. In addition, the percentage of T regulatory cells among CD4 T cells was increased during the same period and was not decreased upon treatment discontinuation. Finally, we show that the ability of T cells to proliferate is transiently reduced after concomitant radiochemotherapy but is restored at the time of adjuvant TMZ cycles. Although not experimentally validated, transient reduction in proliferation associated with strong lymphopenia during radiochemotherapy may suggest that vaccine-induced T cell stimulation would be suboptimal in that period and that therapeutic vaccination should be performed outside radiochemotherapy administration. In addition, strategies aiming at depleting Treg cells should be implemented in future trials.

Dataset Information

Effect of radiochemotherapy on peripheral immune response in glioblastoma.

Background

Methods

Results

Conclusion

Publications

Effect of radiochemotherapy on peripheral immune response in glioblastoma.

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