Evaluation Of The Primary Tumor And Immune Microenvironment In Rectal Cancer After Neoadjuvant Chemoradiotherapy

Propose Neoadjuvant chemoradiotherapy(NCRT),also known as preoperative chemoradiotherapy is now the standard treatment for patients with locally advanced mid-low rectal cancer.Not all tumors show regressive changes in a similar manner.It is observed that patterns of recurrence have changed,with pulmonary being the most common site of recurrence in patients with locally advanced rectal cancer treated with NCRT.It is possible that NCRT may impact the biological behavior of tumor cells,or even change the tumor microenvironment,which may enhancement of invasiveness and metastasis.In this study,we examined the effect of NCRT on the primary tumor cells and microenvironment,and analyze its relationship with response and outcome.Materials and Methods We retrospectively identified rectal cancer patients with locally advanced(c?-c?)rectal cancer who received 5-FU-based chemoradiation followed by radical surgery from our database between 1994 and 2013.The routine H&E stained pathologic slices of resected specimen was reviewed.The immunohistochemical expression profile of 18 markers,including epithelial-mesenchymal transition,cancer stem cell-related markers,tumor infiltrating lymphocyte subgroups,tumor associated macrophage,immune blockade and several cytokines,were examined in postoperative specimens and dichotomised as high or low.Results A total of 329 patients were recruited in this study with a median follow-up of 37.2 months.In non-pCR patients(n=283),ypN stage and TRG were independently associated with 3-year DFS,but ypT stage was not.We developed a new modified T stage classification metric(M-TTRG)with weighting by ?-coefficients from multivariate analyses.The incidence of patients developing local or distant recurrence increased with increasing M-TTRG level.All five M-TTRG classes correlated with 3-year DFS.Our modified ypTNM staging system significantly improved prediction of 3-year DFS.This suggests TRG could complement ypT stage,and we propose the new M-TTRG metric could be used to better classify NCRT-treated patients,thereby improving treatment and assessing prognosis.High expression of CD133,ALDH1,high densities of CD68+macrophage and CD3+,CD4+,CD8+ in the primary tumor were significantly associated with worse DFS in Kaplan-Meier survival analysis.Conclusion TRG could complement ypT stage,and we propose the new M-TTRG metric could be used to better classify NCRT-treated rectal cancer patients,thereby improving treatment and assessing prognosis.NCRT can result in changes in the phenotype of tumor cells,as well as tumor microenvironment,with stem cell enrichment and tumor infiltrating lymphocyte aggregation,which may affect patients' long-term prognosis.