Evaluation of Molecular-level Changes of Programmed Cell Death Ligand-1 after Radiation Therapy in a BALB/c CT26 Colorectal Mouse Tumor Model
Abstract
The effects of radiation therapy (RT) for cancer can be systemic and partially mediated by the immune system. However, radiation alone is unlikely to transform an immunosuppressive environment into an immunostimulatory one. Therefore, an effective combination of RT and immunotherapy may provide a new, more efficient treatment approach. Here, we investigated how the expression of programmed cell death-ligand 1 (PD-L1) in the tumor microenvironment varied in different RT regimens with the same biologically effective dose.
In this study, female BALB/c mice inoculated with CT26 tumor cells were irradiated with 3 different RT regimens using the same BED of 40 gray (Gy). These included ablative RT (1*15 Gy), hypo-fractionated RT (2*10 Gy), and conventional (Hyper-fractionated) RT (10*3 Gy). PD-L1 expression was analyzed with immunohistochemical staining on days 2 and 20 and when the size of tumors had reached 2 cm2 after RT.
All treated groups expressed PD-L1, but the group receiving single ablative high-dose RT showed higher expression compared to the other groups. No significant differences in PD-L1 expression were observed at different times in the same group.
These findings showed that different regimens of RT have different effects on the TME, so a combination of RT and immune checkpoint blockade could be clinically used in cancer patients.
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24. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687–95.
25. Dong W, Wu X, Ma S, Wang Y, Nalin AP, Zhu Z, et al. The Mechanism of Anti–PD-L1 Antibody Efficacy against PD-L1–Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector. Cancer Discov. 2019;9(10):1422–37.
26. Wang T, Zhao Y, Peng L, Chen N, Chen W, Lv Y, et al. Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway. Gut. 2017;66(11):1900–11.
27. Balázs K, Kis E, Badie C, Bogdándi EN, Candéias S, Garcia LC, et al. Radiotherapy-induced changes in the systemic immune and inflammation parameters of head and neck cancer patients. 2019;11(9):1324.
2. Barker HE, Paget JTE, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer. 2015;15(7):409–25.
3. Barcellos-Hoff MH, Park C, Wright EG. Radiation and the microenvironment – tumorigenesis and therapy. Nat Rev Cancer. 2005;5(11):867–75.
4. Walle T, Martinez Monge R, Cerwenka A, Ajona D, Melero I, Lecanda F. Radiation effects on antitumor immune responses: current perspectives and challenges. Ther Adv Med Oncol. 2018;10:175883401774257.
5. Katsuki S, Takahashi Y, Tamari K, Minami K, Takenaka W, Ibuki Y, et al. Radiation therapy enhances systemic antitumor efficacy in PD-L1 therapy regardless of sequence of radiation in murine osteosarcoma. Gangopadhyay N, editor. PLoS One. 2022;17(7):e0271205.
6. Leroi N, Lallemand F, Coucke P, Noel A, Martinive P. Impacts of ionizing radiation on the different compartments of the tumor microenvironment. Fronti Pharmacol. 2016;7:78.
7. Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC. Combinations of immunotherapy and radiation in cancer therapy. Frontiers in oncology. 2014;4:325.
8. Pistillo MP, Carosio R, Banelli B, Morabito A, Mastracci L, Ferro P, et al. IFN-γ upregulates membranous and soluble PD-L1 in mesothelioma cells: potential implications for the clinical response to PD-1/PD-L1 blockade. Cell Mol Immunol. 2020;17(4):410-1.
9. Mimura K, Teh JL, Okayama H, Shiraishi K, Kua L-F, Koh V, et al. PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 2018;109(1):43–53.
10. Fowler JF. 21 Years of biologically effective dose. British Radiol. 2010;83(991):554-68.
11. Alinezhad M, Bakhshandeh M, Rostami E, Alimohamadi R, Mosaffa N, Jalali SA. Synergistic effects of anti-PDL-1 with ablative radiation comparing to other regimens with same biological effect dose based on different immunogenic response. Xue J, editor. PLoS One. 2020;15(4):e0231507.
12. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al. Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade. Cancer Res. 2014;74(19):5458–68.
13. Tang C, Wang X, Soh H, Seyedin S, Cortez MA, Krishnan S, et al. Combining Radiation and Immunotherapy: A New Systemic Therapy for Solid Tumors? Cancer Immunol Res. 2014;2(9):831–8.
14. Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing Tumor Immunity With Fractionated Radiation. Int J Radiat Oncol. 2012;83(4):1306–10.
15. Gandhi SJ, Minn AJ, Vonderheide RH, Wherry EJ, Hahn SM, Maity A. Awakening the immune system with radiation: Optimal dose and fractionation. Cancer Lett. 2015;368(2):185–90.
16. Ghaffari-Nazari H, Tavakkol-Afshari J, Jaafari MR, Tahaghoghi-Hajghorbani S, Masoumi E, Jalali SA. Improving multi-epitope long peptide vaccine potency by using a strategy that enhances CD4+ T Help in BALB/c mice. Vol. 10, PLoS ONE. 2015.
17. Chen JL-Y, Pan C-K, Huang Y-S, Tsai C-Y, Wang C-W, Lin Y-L, et al. Evaluation of antitumor immunity by a combination treatment of high-dose irradiation, anti-PDL1, and anti-angiogenic therapy in murine lung tumors. Cancer Immunol Immunother. 2021;70(2):391–404.
18. Golchin S, Alimohammadi R, Rostami Nejad M, Jalali SA. Synergistic antitumor effect of anti‐PD‐L1 combined with oxaliplatin on a mouse tumor model. J Cell Physiol. 2019;234(11):19866–74.
19. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Science translational medicine. 2012;4(127):127ra37.
20. Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, et al. Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression. Cell Rep. 2017;19(6):1189–201.
21. Demaria S, Formenti SC. Radiation as an immunological adjuvant: current evidence on dose and fractionation. Vol. 2, Front Oncol. 2012.
22. Lan Y, Moustafa M, Knoll M, Xu C, Furkel J, Lazorchak A, et al. Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer Cell. 2021;39(10):1388-1403.e10.
23. Simoni Y, Becht E, Fehlings M, Loh CY, Koo S, Teng KWW, et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 2018;557(7706):575–9.
24. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687–95.
25. Dong W, Wu X, Ma S, Wang Y, Nalin AP, Zhu Z, et al. The Mechanism of Anti–PD-L1 Antibody Efficacy against PD-L1–Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector. Cancer Discov. 2019;9(10):1422–37.
26. Wang T, Zhao Y, Peng L, Chen N, Chen W, Lv Y, et al. Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway. Gut. 2017;66(11):1900–11.
27. Balázs K, Kis E, Badie C, Bogdándi EN, Candéias S, Garcia LC, et al. Radiotherapy-induced changes in the systemic immune and inflammation parameters of head and neck cancer patients. 2019;11(9):1324.
| Files | ||
| Issue | Vol 22 No 2 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i2.12677 | |
| Keywords | ||
| Immunohistochemistry Programmed cell death 1 ligand 1 protein Radio-frequency therapy Tumor microenvironments | ||
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How to Cite
1.
Khani Chamani F, Shabani M, Moradi A, Alinejad M, Jalali SA. Evaluation of Molecular-level Changes of Programmed Cell Death Ligand-1 after Radiation Therapy in a BALB/c CT26 Colorectal Mouse Tumor Model. Iran J Allergy Asthma Immunol. 2023;22(2):163-171.
