Dissecting the inflammatory tumor microenvironment of esophageal adenocarcinoma: mast cells and natural killer cells are favorable prognostic factors and associated with less extensive disease

Abstract

Purpose Esophageal adenocarcinoma (EAC) remains a challenging and lethal cancer entity. A promising target for new therapeutic approaches, as demonstrated by the success of immune checkpoint inhibitors, are tumor-associated immune cells and the tumor microenvironment (TME). However, the understanding of the TME in esophageal cancer remains limited and requires further investigation. Methods Over 900 EAC samples were included, including patients treated with primary surgery and neoadjuvant (radio-)chemotherapy. The immune cell infiltrates of mast cells (MC), natural killer cells (NK cells), plasma cells (PC), and eosinophilic cells (EC) were assessed semi-quantitatively and correlated with histopathological parameters and overall survival (OS). Results A high presence of all four immune cell types significantly correlated with a less extensive tumor stage and a lower frequency of lymph node metastasis, and, in case of NK cells, with less distant metastasis. The presence of MC and NK cells was favorably associated with a prolonged OS in the total cohort (MC: p < 0.001; NK cells: p = 0.004) and patients without neoadjuvant treatment (MC: p < 0.001; NK cells: p = 0.01). NK cells were a favorable prognostic factor in the total cohort (p = 0.007) and in the treatment-naïve subgroup (p = 0.04). Additionally, MC were a favorable prognostic factor in patients with lymph node metastasis (p = 0.009). Conclusion Our results indicate a complex and important role of mast cells, NK cells, and the other assessed immune cells in the tumor microenvironment of EAC. Therefore, they are one further step to a better understanding of the immune cell environment and the potential therapeutic implications in this cancer entity.

Towards personalized management of early esophageal adenocarcinoma

“…In a few retrospective studies, high-grade tumor budding in early EACs has been described as an independent risk factor for LNM and poor prognosis [ 38 , 43 – 45 ]. Moreover, some studies have also reported a significant correlation of certain immune cell types with LNM and survival rates [ 46 ▪ , 47 ▪ , 48 ]. Although our understanding for EAC is still limited, these results might point towards a possibly valuable direction for further research.…”

Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma

“…Lymph node and distant site metastases worsen the prognosis. Lower levels of immune cells, specifically CD8+ T cells, have been associated with higher lymph node invasion ( 17 , 18 , 21 , 36 ). Macrophages tend to have an immunoregulatory phenotype in nodal-spread OAC ( 28 ).…”

“…Several studies describing the TME in OAC associated clinical outcomes to the presence or absence of specific cell populations. It is widely accepted that a higher level of total immune cells, or total tumour-infiltrating lymphocytes, is linked to longer overall survival (OS) independently from the chosen therapeutic approach (17)(18)(19)(20)(21)(22). Derks et al reported OAC had a lower T cell density compared to gastric tumours (23).…”

The Underappreciated Role of Eosinophils in Esophageal Cancer

“… 5 Furthermore, high levels of eosinophils and mast cells each correlate with favorable outcomes in esophageal cancer patients. 7 , 8 , 9 , 10 Notably, however, the direct role of eosinophils in ESCC has remained elusive.…”

“…Of course, although the current study shows that eosinophils promote apoptosis in ESCC cells in vitro, it will be imperative to determine whether eosinophils are capable of inducing ESCC regression in vivo. Because eosinophilia also has been detected in subsets of patients with Barrett’s esophagus or esophageal adenocarcinoma, 10 , 12 it will be of further interest to determine if eosinophils exert antitumor activity in this context as well. The technical feasibility of harnessing the antitumor activity of eosinophils in esophageal cancer lesions also represents an important consideration.…”