Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy
Abstract
:1. Introduction
2. Results
2.1. Comparison of Matched Primary and Recurrent GBM Tumors
2.1.1. Patient and Tumor Characteristics
2.1.2. TAM Infiltration Is Significantly Reduced in Recurrent Tumors and Very High Infiltration Leads to a Reduced PFS
2.1.3. Comparable Angiogenic Activity in Primary and Recurrent Tumors
2.1.4. TAMs Serve as a Predictor for a Reduced OS
2.2. Potential Effects of TMZ Treatment on the Tumor Microenvironment
Expression of Proangiogenic Molecules and Vascularization in GBM Patients Is Mostly Not Affected by TMZ Therapy
2.3. In Vivo Assessment of Combination Therapy with TMZ and SB
2.3.1. No Adverse Effects by Additional CXCR2 Antagonization with TMZ In Vivo
2.3.2. Combination Therapy with TMZ and SB Reduces Tumor Volume and Proliferation in a Syngeneic Orthotopic GBM Mouse Model
2.3.3. Combination Therapy with TMZ and SB Tends to Diminish Total Tumor Vascularization While Infiltration of TAMs Was Unaltered
2.3.4. CXCR2/CXCL2 Are Upregulated in Murine Tumor Tissue and Decreased by Therapy without Affecting Alternative Signaling Pathways
3. Discussion
3.1. Comparison of Matched Primary and Recurrent GBM Tumor Characteristics
3.2. TAMs Serve as a Negative Predictor of OS in GBM
3.3. The Influence of TMZ on Central Chemokines in GBM
3.4. Combination Therapy Leads to Superior Antitumoral Effects Compared to Sole TMZ In Vivo
3.5. Limitations
4. Materials and Methods
4.1. Human Specimens
Immunofluorescence Staining of Human FFPE Sections
4.2. In Vivo Animal Model
4.2.1. Tumor Cells
4.2.2. Animals and Set-Up
4.2.3. Treatments
4.2.4. MRI
4.2.5. Tissue Harvesting and Preparation for Analysis
4.2.6. Immunofluorescence Staining of Mouse Brain Sections
4.2.7. RNA Isolation and Quantitative Real-Time PCR
4.3. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patient Features | n | ||
female | 13 * (34%) | ||
male | 25 * (66%) | ||
mean age at diagnosis in years | 59 ± 13 | ||
median age at diagnosis in years | 61 (21–82) | ||
Treatment | |||
primary tumor resection | 38 * (100%) | ||
tmz cycles | ≥4 | 18 * (47%) | |
1–3 | 8 * (21%) | ||
0 | 12 * (32%) | ||
Survival | |||
PFS (months) | mean | 12 ± 9 | |
median | 9 (2–36) | ||
OS (months) | mean | 19 ± 10 | |
median | 17 (2.4–42.5) | ||
Histopathologic Features | |||
GBM samples | 76 (100%) | ||
MGMT status | unmethylated | 22 (58%) * | |
methylated | 16 (42%) * | ||
IDH1 status | mutated | 1 (2.6%) * | |
wildtype | 37 (97.4%) * | ||
Ki-67 (mitotic index) | pGBM | rGBM # | |
<10% | 2 (5.3%) | 7 (20%) | |
10–30% | 32 (84.2%) | 26 (74.3%) | |
>30% | 4 (10.5%) | 2 (5.7%) | |
p53 accumulation | positive | 34 (89.5%) | 26 (81.25%) |
negative | 4 (10.5%) | 6 (18.75%) |
OS | Univariable Analysis | Multiple Analysis | ||||
---|---|---|---|---|---|---|
p-Value | HR | 95% CI | p-Value | HR | 95% CI | |
pIBA1 | 0.02 | 1.01 | 1.00–1.03 | 0.02 | 1.01 | 1.00–1.03 |
pVEGF | 0.57 | 1.07 | 0.85–1.33 | |||
pCXCL2 | 0.60 | 1.04 | 0.85–1.22 | |||
pIL8 | 0.57 | 0.80 | 0.37–1.73 | |||
pvessel count | 0.77 | 1.00 | 0.99–1.02 | |||
pvessel area | 0.45 | 0.00 | 0.00–1,873,571.60 | |||
pCXCR2+ vessels | 0.72 | 1.00 | 0.99–1.02 | |||
pCXCR2+ vessel area | 0.12 | 0.00 | 0.00–8874 × 1022 | 0.04 | 0.00 | 0.00–0.001 |
TMZ cycles | 0.20 | 0.94 | 0.86–1.03 | 0.07 | 0.86 | 0.73–1.01 |
MGMT methylation | 0.30 | 0.99 | 0.96–1.01 |
PFS | Univariable Analysis | Multiple Analysis | ||||
---|---|---|---|---|---|---|
p-Value | HR | 95% CI | p-Value | HR | 95% CI | |
pIBA1 | 0.60 | 1.00 | 0.99–1.00 | |||
pVEGF | 0.35 | 0.90 | 0.73–1.12 | |||
pCXCL2 | 0.29 | 1.08 | 0.93–1.26 | |||
pIL8 | 0.60 | 0.82 | 0.39–1.72 | |||
pvessel count | 0.48 | 1.01 | 0.99–1.02 | |||
pvessel area | 0.49 | 1114.81 | 0.00–6.63 × 1011 | |||
pCXCR2+ vessels | 0.25 | 0.99 | 0.98–1.01 | |||
pCXCR2+ vessel area | 0.32 | 0.00 | 0.00–4.34 × 1041 | |||
TMZ cycles | 0.01 | 0.86 | 0.77–0.96 | 0.02 | 0.87 | 0.78–0.98 |
MGMT methylation | 0.04 | 0.97 | 0.94–0.99 | 0.09 | 0.98 | 0.95–1.00 |
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Urbantat, R.M.; Jelgersma, C.; Brandenburg, S.; Nieminen-Kelhä, M.; Kremenetskaia, I.; Zollfrank, J.; Mueller, S.; Rubarth, K.; Koch, A.; Vajkoczy, P.; et al. Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy. Int. J. Mol. Sci. 2021, 22, 11180. https://doi.org/10.3390/ijms222011180
Urbantat RM, Jelgersma C, Brandenburg S, Nieminen-Kelhä M, Kremenetskaia I, Zollfrank J, Mueller S, Rubarth K, Koch A, Vajkoczy P, et al. Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy. International Journal of Molecular Sciences. 2021; 22(20):11180. https://doi.org/10.3390/ijms222011180
Chicago/Turabian StyleUrbantat, Ruth M., Claudius Jelgersma, Susan Brandenburg, Melina Nieminen-Kelhä, Irina Kremenetskaia, Julia Zollfrank, Susanne Mueller, Kerstin Rubarth, Arend Koch, Peter Vajkoczy, and et al. 2021. "Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy" International Journal of Molecular Sciences 22, no. 20: 11180. https://doi.org/10.3390/ijms222011180