Schäfer A, Zülch L, Steinsdörfer L, Donaubauer AJ, Reichardt C, Frey B, Fietkau R, Haderlein M, Corradini S, Gaipl U, Jost T (2026)
Publication Type: Journal article
Publication year: 2026
Book Volume: 179
Article Number: 108019
DOI: 10.1016/j.oraloncology.2026.108019
Background: Even in the area of immune therapies, multimodal treatment of head and neck squamous cell carcinoma (HNSCC) is a big challenge. Small molecule kinase inhibitors (smKI), that target the DNA damage repair (DDR) system, have been described to alter, in addition to their radio-sensitizing effects, the immune phenotype of HNSCC. Thereby, the ATM and ATR kinases are key mediators of the DDR. However, the consequences these changes of the tumor cell phenotype have on immune cells are still poorly understood. Consequently, we here investigated how single and combination treatment of HNSCC cells with an ATM (ATMi) or an ATR inhibitor (ATRi) in combination with hypo-fractionated radiotherapy (RT) differently affects the activation of human cytotoxic CD8 + T cells regarding proliferation, activation marker surface expression and cytokine secretion. Methods: Human papillomavirus (HPV)-negative (Cal-33, HSC4) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC tumor cells were treated with hypo-fractionated RT of 2 x 5 Gray (Gy) in combination with AZD0156 (ATMi) or VE-822 (ATRi) and co-cultured with human CD8 + T cells for 96 h. T cell activation was quantified by CFSE-signal detected proliferation rates, activation marker expression on surfaces of the T cells, and by secretion of interferon gamma (IFN-γ) in the supernatants of the co-cultures via ELISA. Results: In 2D co-cultivation settings RT-, HPV-status- and inhibitor-dependent influences on Tcell activation were observed. Thereby, a stronger activation of T cells could be achieved after co-cultivation with ATRi-treated HNSCC tumor cells compared to ATMi. However, the addition of immune checkpoint inhibitors did not lead to enhanced T cell activation. In 3D co-cultures, a shift from RT-induced to a more inhibitor-induced effect on human T cells was visible and confirmed the superiority of ATRi, especially in combination with additional RT. Conclusion: The combination of RT + ATRi resulted in increased T cell activation compared to the combined treatment with ATMi, respectively. This suggests an advantage of ATRi in comparison to ATMi in combination with RT for induction of beneficial anti-tumor immune responses in HNSCC.
APA:
Schäfer, A., Zülch, L., Steinsdörfer, L., Donaubauer, A.-J., Reichardt, C., Frey, B.,... Jost, T. (2026). ATR inhibition in combination with hypofractionated radiotherapy is superior to ATM inhibition with regard to ex vivo CD8 + T cell activation particularly for HPV-negative head and neck cancer cells. Oral Oncology, 179. https://doi.org/10.1016/j.oraloncology.2026.108019
MLA:
Schäfer, Anna, et al. "ATR inhibition in combination with hypofractionated radiotherapy is superior to ATM inhibition with regard to ex vivo CD8 + T cell activation particularly for HPV-negative head and neck cancer cells." Oral Oncology 179 (2026).
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