Preoperative chemoradiotherapy induces multiple pathways related to anti-tumour immunity in rectal cancer
Menée à l'aide de lignées cellulaires d'adénocarcinome colorectal, d'échantillons biopsiques et de pièces de résection prélevés sur 27 patients atteints d'un cancer du rectum, cette étude met en évidence l'effet d'une chimioradiothérapie pré-opératoire sur de multiples voies liées à l'immunité antitumorale
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 IFN
β 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
β 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.