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

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.

A three-phase trans-ethnic study reveals B7-H3 expression is a significant and independent biomarker associated with colon cancer overall survival

“…Elevated expression of B7H3 has been found in serum of patients with malignant tumors, which is related to clinical stage and progression of cancer (49,50), since B7-H3 appears to be correlated with different proteins that contribute to tumor migration, invasion and angiogenesis (51,52). Besides, B7-H3 blocking in combination with chemotherapy is a promising treatment option based on preclinical animal studies (53). Currently, some previous studies have described a significant correlation between tumor expression of B7-H3 and prognosis (14,54), whereas, majority of them reported that high tumor B7-H3 expression was associated with more advanced disease (31), increased risk of recurrence (35) or shorter survival time (55), which was consistent with our results.…”

Tissue-Based Markers as a Tool to Assess Response to Neoadjuvant Radiotherapy in Rectal Cancer—Systematic Review

“…In 2020, Yasui et al published a study whose aim was to investigate the effect of chemoradiotherapy on the immunological status of rectal cancer patients who were treated with preoperative chemoradiotherapy. The results demonstrated that the expression of immune checkpoint genes, such as B7-H3 and B7-H5, was upregulated after chemoradiotherapy [ 113 ]. Therefore, it can be supposed that B7 family checkpoint molecules could be used as predictors of response to chemoradiotherapy in colorectal cancer patients.…”

A new immunocompetent rectal cancer model to study radiation therapy

“…We next examined changes in the TME to evalaute if our model recapatituates changes in the TME in response to RT in human patients. Pior work has show a significant increase in M2 macrophage polarization post RT 14 . Similarly, when examining the TME of mice with AKP endoluminal tumors we observed a signfiant increase in macrophage infiltration (detected by macrophage surface marker F4/80) and M2 polarization (CD206 + F4/80 + ), but not M1 (CD11c + F4/80 + ) ( Fig.…”