Multiplexed Immunofluorescence Imaging Reveals an Immune-Rich Tumor Microenvironment in Mucinous Rectal Cancer Characterized by Increased Lymphocyte Infiltration and Enhanced Programmed Cell Death Protein 1 Expression

Abstract

BACKGROUND:Mucinous rectal cancer is associated with a higher incidence of microsatellite instability and a poorer response to neoadjuvant chemoradiotherapy compared to other subtypes of rectal adenocarcinoma. Immune checkpoint inhibitors are an emerging family of anticancer therapeutics associated with highly variable outcomes in colorectal cancer. Although the immune landscape of mucinous rectal cancer has not been fully explored, the presence of mucin is thought to act as a barrier preventing immune-cell infiltration. OBJECTIVE:The aim of this study was to determine the immune properties of mucinous rectal cancer and investigate the degree of lymphocyte infiltration in this cohort.DESIGN: This is a retrospective cohort study that involved multiplexed immunofluorescence staining of tumor microarrays. SETTINGS:Samples originated from a single university teaching hospital. PATIENTS:Our cohort included 15 cases of mucinous and 43 cases of nonmucinous rectal cancer. MAIN OUTCOME MEASURES:Immune cells were classified and quantified. Immune-cell counts were compared between mucinous and nonmucinous cohorts. Immune marker expression within tumor epithelial tissue was evaluated to determine the degree of lymphocyte infiltration.

Multi-dataset study on neoadjuvant treatment-related prognostic model and molecular network mechanism of locally advanced rectal cancer

“…This process involves the aberrant regulation of signaling pathways and the crucial role of immune in ltration. At the molecular biology level, dysregulation of various signaling pathways, such as Wnt, MAPK, and PI3K/Akt, results in uncontrolled tumor cell proliferation and impaired apoptotic mechanisms, thereby exacerbating the progression of rectal cancer [28][29][30]. Furthermore, these dysregulated signaling pathways contribute to tumor invasion and migration, providing a molecular basis for metastasis.…”

Implications of Rectal Cancer Radiotherapy on the Immune Microenvironment: Allies and Foes to Therapy Resistance and Patients’ Outcome

“…Previous animals models using colon cancer cell lines (MC38 and CT26) suggested that PD-1 upregulation on T cells following (C)RT has rather unfavorable effects on T cell activation and anti-tumor response [199,233]. In human mucinous rectal cancer patients, the use of nCRT and high PD-1 were positively correlated [234]. Furthermore, in a small study including 13 LARC patients who had received SCRT, it could be found that poor responders had an increased number of CD4 + /CD25 hi+ /FOXP3 + /PD-1 + Tregs infiltrating the tumors compared to good responders [198].…”

Rectal Cancer: New Challenges

“…Kim et al 7 evaluated the effect of lymphatic, venous, and perineural invasion and tumor budding on 5-year disease-free and overall survival in patients with LARC undergoing neoadjuvant chemoradiation. Duggan et al 8 reported a study aiming to characterize the immune microenvironment of mucinous rectal cancers in hopes of better defining potential therapeutic targets. Engel et al 9 conducted a retrospective analysis from an Australian cancer database from 3 institutions to determine the prognostic effect of anastomotic leak on disease-free and overall survival.…”