Preoperative chemoradiotherapy induces multiple pathways related to anti-tumour immunity in rectal cancer

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, beta 2-microglobulin, TAP1, PD-L1 and STING/IFN beta 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 IFN beta 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, IFN beta and the downstream genes (MX1, MX2, UBE2L6v2, IFI6v2 and IFI44) mRNA levels significantly increased after 3 x 8 Gy or 1 x 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.

Automated summary

Preoperative radiotherapy can induce changes in the immune phenotype of rectal cancer cells, resulting in the restoration of HLA-class-I expression and the induction of IFN-beta and PD-L1 expression. This suggests that radiotherapy may enhance the efficacy of immunotherapy.