Abstract
Cytotoxic CD8+ T (Tc) cells are the main executors of transformed and cancer cells during cancer immunotherapy. The latest clinical results evidence a high efficacy of novel immunotherapy agents that modulate Tc cell activity against bad prognosis cancers. However, it has not been determined yet whether the efficacy of these treatments can be affected by selection of tumoural cells with mutations in the cell death machinery, known to promote drug resistance and cancer recurrence. Here, using a model of prophylactic tumour vaccination based on the LCMV-gp33 antigen and the mouse EL4 T lymphoma, we analysed the molecular mechanism employed by Tc cells to eliminate cancer cells in vivo and the impact of mutations in the apoptotic machinery on tumour development. First of all, we found that Tc cells, and perf and gzmB are required to efficiently eliminate EL4.gp33 cells after LCMV immunisation during short-term assays (1–4 h), and to prevent tumour development in the long term. Furthermore, we show that antigen-pulsed chemoresistant EL4 cells overexpressing Bcl-XL or a dominant negative form of caspase-3 are specifically eliminated from the peritoneum of infected animals, as fast as parental EL4 cells. Notably, antigen-specific Tc cells control the tumour growth of the mutated cells, as efficiently as in the case of parental cells. Altogether, expression of the anti-apoptotic mutations does not confer any advantage for tumour cells neither in the short-term survival nor in long-term tumour formation. Although the mechanism involved in the elimination of the apoptosis-resistant tumour cells is not completely elucidated, neither necroptosis nor pyroptosis seem to be involved. Our results provide the first experimental proof that chemoresistant cancer cells with mutations in the main cell death pathways are efficiently eliminated by Ag-specific Tc cells in vivo during immunotherapy and, thus, provide the molecular basis to treat chemoresistant cancer cells with CD8 Tc-based immunotherapy.
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Acknowledgements
We would like to thank Daniele Lecis for kindly providing the SMAC mimetic SM-83. This work was supported in part by Fondo Social Europeo (JP) and Ministerio de Economia y Competitividad (SAF2011-25390 (JP), SAF2014-54763-C2-1 (JP) and SAF2017‐83120‐C2‐1‐R). Predoctoral grants/contracts from Fundación Santander/Universidad de Zaragoza (LS and MA), Gobierno de Aragon (DM, LS and PJS) and FPU/Ministerio de Educación, Cultura y Deportes (PML). IUM was supported by Fondo Garantía Empleo Juvenil/INAEM. Julián Pardo was supported by Fundación Aragon I + D (ARAID). Authors would like to acknowledge the use of Servicios Científico Técnicos del CIBA (IACS-Universidad de Zaragoza) and Servicios Apoyo Investigación de la Universidad de Zaragoza.
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These authors share first authorship: Paula Jaime-Sánchez, Elena Catalán.
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Jaime-Sánchez, P., Catalán, E., Uranga-Murillo, I. et al. Antigen-specific primed cytotoxic T cells eliminate tumour cells in vivo and prevent tumour development, regardless of the presence of anti-apoptotic mutations conferring drug resistance. Cell Death Differ 25, 1536–1548 (2018). https://doi.org/10.1038/s41418-018-0112-9
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DOI: https://doi.org/10.1038/s41418-018-0112-9
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