Characterization of chemoradiation-induced changes in immune cells and targets for personalized therapy in locally advanced rectal cancer (LARC).

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589 Background: Neoadjuvant radio/chemoradiotherapy (CRT) is a treatment milestone for LARC. The importance of immune response in CRT efficacy is increasingly realised. However immune cell changes associated with poor responders and their modulation with immune-CRT combinations is unclear. Methods: Matched archival pre-CRT biopsies and post-CRT resection specimens from patients (pts) treated with neoadjuvant CRT were retrieved. Delta-TCD (tumor cell density, estimated using quantitative point counting on virtual tissue H&E) and k-means clustering method were used to classify pts into good, intermediate and poor responders. Baseline expression and CRT-induced changes in 770 immune-related genes (plus 30 DNA damage response genes) were evaluated using NanoString Technologies. Results: At least 70 pts treated with short/long course radiotherapy (SCRT/LCRT) and matched tissues available were identified. To date, 27 pts evaluable for deltaTCD and gene expression were clustered into good (n:10), intermediate (n:7) and poor (n:10) responders. The expression of 14% (91/636) of immune genes was significantly affected by CRT (Bonferroni t-test, q-value < 0.05) overall, with significant increase in innate immunity and decrease in adaptive immunity across all pts (CIBERSORT and SSGSEA analyses). Between good and poor responders there were 6% (39/636) and 2% (15/636) of genes significantly affected by CRT (Bonferroni t-test, q-value < 0.05), respectively. CRT-induced increased CD8+ T cells expression in poor responders compared to good responders was seen. Increased baseline expression of resistance genes (including PD-L1, IDO1 and IL2RA) were seen in poor versus good responders. Validation with quantitative multiplex-immunofluorescence (Vectra) and correlation with SCRT/LCRT and time to surgery are on-going. Conclusions: The expression of immune-related genes is significantly modified by CRT in LARC. With the caveat of small numbers, we identified differentially expressed immune targets at baseline which may justify immune-CRT combinations in neoadjuvant setting in selected pts to modulate the CRT effect and ultimately increase response.