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Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer. BJS 2019; 106: 1381-1392.

Published: 13th June 2019

Authors: T. Akiyoshi, N. Tanaka, K. Kiyotani, O. Gotoh, N. Yamamoto, K. Oba et al.

Background

Accumulating evidence suggests that radiotherapy success has an immune‐associated component. The immunogenomic profiles associated with responses to chemoradiotherapy (CRT) were assessed in patients with locally advanced rectal cancer in this study.

Method

CD8+ tumour‐infiltrating lymphocyte (TIL) and stromal lymphocyte densities were assessed by immunohistochemistry using pretreatment biopsies from patients with advanced rectal cancer who had preoperative CRT. Whole‐exome sequencing and gene expression microarray analysis were conducted to investigate the genomic properties associated with the response to CRT and CD8+ TIL density. Response to CRT was determined based on Dworak tumour regression grade (TRG); tumours with complete (TRG 4) or near‐complete (TRG 3) regression were grouped as good responders, and those with TRG 1 as non‐responders.

Results

Immunohistochemical examinations (275 patients) showed that pre‐CRT CD8+ TIL density was associated with better response to CRT and improved recurrence‐free survival, whereas pre‐CRT stromal CD8+ cell density was not associated with either response to CRT or recurrence‐free survival. Whole‐exome sequencing (74 patients) showed that the numbers of single‐nucleotide variations (SNVs) and neoantigens predicted from SNVs were higher in good responders than in non‐responders, and these correlated positively with CD8+ TIL density (rS = 0·315 and rS = 0·334 respectively). Gene expression microarray (90 patients) showed that CD8A expression correlated positively with the expression of programmed cell death 1 (PDCD1) (rS = 0·264) and lymphocyte‐activation gene 3 (LAG3) (rS = 0·507).

Conclusion

Pre‐CRT neoantigen‐specific CD8+ T cell priming may be a key event in CRT responses where immune checkpoint molecules could be useful targets to enhance tumour regression.

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