Effect of preoperative chemoradiotherapy on the immunological status of rectal cancer patients

• Published in: Journal of radiation research Vol. 61; no. 5; pp. 766 - 775
• Main Authors: Yasui, Kazuaki, Kondou, Ryota, Iizuka, Akira, Miyata, Haruo, Tanaka, Emiko, Ashizawa, Tadashi, Nagashima, Takeshi, Ohshima, Keiichi, Urakami, Kenichi, Kusuhara, Masatoshi, Muramatsu, Koji, Sugino, Takashi, Yamguchi, Ken, Mori, Keita, Harada, Hideyuki, Nishimura, Tetsuo, Kagawa, Hiroyasu, Yamakawa, Yushi, Hino, Hitoshi, Shiomi, Akio, Akiyama, Yasuto
• Format: Journal Article
• Language: English
• Published: Oxford University Press 01.09.2020
• Subjects: Analysis; Cancer; Cancer patients; Care and treatment; Chemotherapy; Colon cancer; Genes; Genetic aspects; Immune response; Immunohistochemistry; Metastasis; Regular Paper; Stem cells; Transforming growth factors; Japan; consensus molecular subtype (CMS); chemoradiotherapy (CRT); tumor microenvironment (TME); tumor-infiltrating lymphocytes (TIL); epithelial-to-mesenchymal transition (EMT)
• ISSN: 0449-3060; 1349-9157
• DOI: 10.1093/jrr/rraa041

Abstract The aim of the study was to investigate the effect of chemo-radiation on the genetic and immunological status of rectal cancer patients who were treated with preoperative chemoradiotherapy (CRT). The expression of immune response-associated genes was compared between rectal cancer patients treated (n = 9) and not-treated (n = 10) with preoperative CRT using volcano plot analysis. Apoptosis and epithelial-to-mesenchymal transition (EMT) marker genes were analysed by quantitative PCR (qPCR). Other markers associated with the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TIL) and immune checkpoint molecules, were investigated using immunohistochemistry (IHC). The clinical responses of preoperative CRT for 9 rectal cancer patients were all rated as stable disease, while the pathological tumor regression score (TRG) revealed 6 cases of grade2 and 3 cases of grade1. According to the genetic signature of colon cancers, treated tumors belonged to consensus molecular subtype (CMS)4, while not-treated tumors had signatures of CMS2 or 3. CRT-treated tumors showed significant upregulation of EMT-associated genes, such as CDH2, TGF-beta and FGF, and cancer stem cell-associated genes. Additionally, qPCR and IHC demonstrated a suppressive immunological status derived from the upregulation of inflammatory cytokines (IL-6, IL-10 and TGF-beta) and immune checkpoint genes (B7-H3 and B7-H5) and from M2-type macrophage accumulation in the tumor. The induction of EMT and immune-suppressive status in the tumor after strong CRT treatment urges the development of a novel combined therapy that restores immune-suppression and inhibits EMT, ultimately leading to distant metastasis control.