Abstract
Background
Rectal cancer treated with preoperative radiotherapy (RT) provides an interesting model to study changes induced on cancer cell immuno-phenotype that could be exploited by immunotherapy interventions to improve prognosis.
Materials and methods
We assessed the expression of HLA-class-I, β2-microglobulin, TAP1, PD-L1 and STING/IFNβ in preoperative biopsies and respective post-RT surgical specimens from patients with rectal cancer (n = 27). The effect of radiation was further investigated in colorectal adenocarcinoma cell lines HT-29 and Caco-2.
Results
Rectal carcinomas exhibited extensive loss of expression of HLA-Class-I related molecules, which was restored in post-irradiation surgical specimens (P < 0.0001). RT induced the expression of IFNβ and STING in cancer cells and tumour-infiltrating lymphocytes (P < 0.0001). In in vitro experiments, irradiation with 4 Gy or 10 Gy induced the expression of HLA-class-I protein (P < 0.001). PD-L1 levels were transiently induced for two days (P < 0.001). cGAS, STING, IFNβ and the downstream genes (MX1, MX2, UBE2L6v2, IFI6v2 and IFI44) mRNA levels significantly increased after 3 × 8 Gy or 1 × 20 Gy irradiation (P < 0.001). TREX1 mRNA levels remained unaltered.
Conclusions
RT induces the IFN-type-I pathway and the expression of HLA-class-I molecules on rectal carcinoma. The transient induction of PD-L1 expression suggests that long-course daily RT may sustain increased PD-L1 levels. Anti-PD-L1/PD-1 immunotherapy could block this immunosuppressive pathway.
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Data availability
All data reported in the study are available for review.
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Acknowledgements
The study has been conducted in the context of the ongoing PhD thesis by IMK. AZ, DT and VK are members of the PhD supervising committee.
Funding
The study has been financially supported by the Democritus University of Thrace Special Account, project no 81006. Additional funding was provided by IMK in the context of his ongoing PhD thesis.
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Contributions
IMK: conception and design, analysis and interpretation of data, immunohistochemical assessment, writing of the first draft and approval of the final draft. EX: in vitro studies analysis and interpretation, drafting the manuscript and approval of the final draft. TIS: flow cytometry experiments, analysis and interpretation, drafting the manuscript and approval of the final draft. MK: immunohistochemical assessment, drafting the manuscript and approval of the final draft. AG: immunohistochemical assessment, analysis and interpretation of the data, drafting the manuscript and approval of the final draft. VK: conception and design, analysis and interpretation of data, critical review of the draft for important intellectual content and approval of the final draft. DT: study supervision, conception and design, analysis and interpretation of the data, critical review of the draft for important intellectual content and approval of the final draft. AZ: study supervision, conception and design, analysis and interpretation of the data, critical review of the draft for important intellectual content and approval of the final draft.
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The Ethics and Research Committee of the Aretaieion University Hospital approved the study (316/26–03–2021), and all patients gave their written informed consent. The study was conducted according to the criteria set by the declaration of Helsinki.
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Koukourakis, I.M., Xanthopoulou, E., Sgouras, T.I. et al. Preoperative chemoradiotherapy induces multiple pathways related to anti-tumour immunity in rectal cancer. Br J Cancer 129, 1852–1862 (2023). https://doi.org/10.1038/s41416-023-02459-9
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DOI: https://doi.org/10.1038/s41416-023-02459-9