High infiltration of B cells in tertiary lymphoid structures, TCR oligoclonality, and neoantigens are part of esophageal squamous cell carcinoma microenvironment

Abstract

Esophageal squamous cell carcinoma (ESCA) exhibits high intratumoral molecular heterogeneity posing a challenge to cancer therapy. Immune checkpoint blockade therapy has been approved for this disease, but with modest results. RNA-Seq data from paired tumor and surrounding nonmalignant tissue from 14 patients diagnosed with ESCA without previous treatment and from The Cancer Genome Atlas-ESCA cohort were analyzed. Herein, we investigated ESCA immune landscape including mutation-derived neoantigens and immune cell subpopulations. Tumor-associated antigen expression was determined by in silico analyses and confirmed by immunohistochemistry showing that PRAME, CEACAM4, and MAGEA11 proteins are expressed on tumors. Immune checkpoint molecules gene expression was higher in the tumor compared with surrounding nonmalignant tissue, but its expression varies greatly among patients. TCR repertoire and BCR transcripts analysis evidenced low clonal diversity with one TCR clone predicted to be specific for a MAGEA11-derived peptide. A high number of B-cell clones infiltrating the tumors and the abundance of these cells in tertiary lymphoid structures observed in ESCA tumors support B cells as a potential immune modulator in this tumor.

Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2)

“…Especially, the predictive value of activated B lymphocytes is supported by an emerging role of B cells and tertiary lymphoid structures (TLS) in tumors, which have been recently reported in association with survival, even in tumor with low T-cell infiltration [28][29][30] . Furthermore, T-follicular helper cells have been shown to play important roles in the generation of TLS in the tumor microenvironment 31 , which might be relatively enriched for B-cell signatures and TLS in ESCC 32 . Thus, the potential relevance of TLS in the mode of action of cancer immunotherapy to mount an efficient antitumor response is supported by our study and warrants further investigation.…”

Key sunitinib‐related biomarkers for renal cell carcinoma

“…Additionally, CEACAM4 which is expressed in primary human granulocytes was reported to be involved in systemic inflammation 53–55 . Moreover, CEACAM4 has been validated to be associated with esophageal squamous cell carcinoma 56 and medullary thyroid carcinoma 51 . All of these indicated CEACAM4 was highly related to both immune and tumor.…”

Upper Aerodigestive Tract Squamous Cell Carcinomas Show Distinct Overall DNA Methylation Profiles and Different Molecular Mechanisms behind WNT Signaling Disruption

“…This might be associated both with tumor cell epigenetic clonality and variations of the stromal and immune cell component, as shown in Figure S3 and previously assessed by other authors [ 89 , 90 ]. Indeed, the immune infiltrate, usually assessed by gene expression levels, was already shown to vary among ESCC and HNSCC patients [ 91 , 92 , 93 ] and might explain, at least in part, tumor heterogeneity in terms of DNA methylation profile. The number of samples analyzed was limited and we were not able to evaluate the impact of etiological factors on the DNA methylation profiles identified due to the quite homogeneous characteristics of patients, mostly heavy smokers, heavy drinkers and HPV-negative.…”