Immunological features of resected tumor after neoadjuvant chemotherapy (NAC) and chemoradiotherapy (CRT) become the superior prediction markers for recurrence in rectal cancer

Background: Although CRT is the standard neoadjuvant therapy for local advanced rectal cancer (RC), benefits of NAC have also been reported recently. In this study, we investigate whether the tumor microenvironment is related to local therapeutic effects and recurrence free survival (RFS) after neoadjuvant therapy, and explore the role of the anti-tumor immune response in cancer treatment. Methods: 200 RC patients were enrolled and categorized into three groups according to pretreatment: CRT (n = 48, 5-Fluorouracil or Capecitabine + Radiation), NAC (n = 51, FOLFOX), Surgery alone (n = 101). The infiltration and status of immune cells were assessed by multiplex fluorescence immunohistochemically analysis. Results: The growth of residual tumor cells after treatment was evaluated using Ki67 expression. Compared with the surgery group, CRT, but not NAC, significantly decreased the percentage of Ki67high cells in cytokeratin positive cells. However, the percentage of Ki67high tumor cells is comparable between all tumor regression grade (TRG) groups. Assessing the immunological features of tumor tissues, we found that the infiltration of T cells into tumors is significantly higher in TRG 1 patients than in patients with TRG 2, 3, and those treated with surgery alone. The percentage of tumor infiltration in Ki67high population of CD4 and CD8 T cells is more prominent, suggesting that aggressive infiltration of T cells might be involved in the treatment effect of neoadjuvant therapies. Notably, in the NAC group, patients with high accumulation of Ki67high CD8 T cells in tumor and stroma tissue experienced long term RFS, compared with patients with low accumulation of Ki67high CD8 T cells. On the other hand, after neoadjuvant therapy with CRT, patients with high accumulation of both CD8 and Ki67high CD4 T cells in tumor achieved long term RFS. Conclusions: Our results suggested that CRT and NAC had different effects on the tumor microenvironment. The densities of Ki67high CD8 T cells in tumors could be a strong inhibitor of recurrence for RC after NAC. In the case of CRT, the densities of CD8 T cells and Ki67high CD4 T cells in tumors could inhibit recurrence. Legal entity responsible for the study: National Cancer Center Hospital East Funding: National Cancer Center Research and Development Fund (28-A-8) Disclosure: All authors have declared no conflicts of interest.