Activated Eosinophils Exert Antitumorigenic Activities in Colorectal Cancer

Abstract

Immunotherapies targeting T lymphocytes are revolutionizing cancer therapy but only benefit a subset of patients, especially in colorectal cancer. Thus, additional insight into the tumor microenvironment (TME) is required. Eosinophils are bone marrow–derived cells that have been largely studied in the context of allergic diseases and parasite infections. Although tumor-associated eosinophilia has been described in various solid tumors including colorectal cancer, knowledge is still missing regarding eosinophil activities and even the basic question of whether the TME promotes eosinophil recruitment without additional manipulation (e.g., immunotherapy) is unclear. Herein, we report that eosinophils are recruited into developing tumors during induction of inflammation-induced colorectal cancer and in mice with the Apcmin/+ genotype, which develop spontaneous intestinal adenomas. Using adoptive transfer and cytokine neutralization experiments, we demonstrate that the TME supported prolonged eosinophil survival independent of IL5, an eosinophil survival cytokine. Tumor-infiltrating eosinophils consisted of degranulating eosinophils and were essential for tumor rejection independently of CD8+ T cells. Transcriptome and proteomic analysis revealed an IFNγ-linked signature for intratumoral eosinophils that was different from that of macrophages. Our data establish antitumorigenic roles for eosinophils in colorectal cancer. These findings may facilitate the development of pharmacologic treatments that could unleash antitumor responses by eosinophils, especially in colorectal cancer patients displaying eosinophilia.

Deciphering the role of eosinophils in solid organ transplantation

“…36,37 In mouse models of colorectal cancer, where IFN-γ is increased, eosinophils directly kill tumors independent of CD8 + T cell functions. 38 This supports findings in colorectal patients where eosinophils correlate with better prognosis and fewer metastases. 39 Alternatively, in melanoma CD8 + T cell recruitment is enhanced by IFN-γ and tumor necrosis factor α (TNF-α) activated eosinophils, resulting in melanoma tumor killing.…”

“…For example, in oral squamous cell carcinoma, it has been proposed that early‐stage carcinoma, which is a Th1‐type microenvironment, leads to anti‐tumorigenic activation of eosinophils while later stages of carcinoma develop a Th2‐type microenvironment and promote pro‐tumorigenic potential of eosinophils . In mouse models of colorectal cancer, where IFN‐γ is increased, eosinophils directly kill tumors independent of CD8 + T cell functions . This supports findings in colorectal patients where eosinophils correlate with better prognosis and fewer metastases .…”

Eosinophil accumulation predicts response to melanoma treatment with immune checkpoint inhibitors

“…39 Furthermore, it has been recently demonstrated an IFN-γ-linked signature in eosinophils infiltrating mouse colorectal tumors and showing a strong anti-tumor activity. 40 IL-2 has been demonstrated to be upregulated in a melanoma mouse model after treatment with ICI 41 and in patients responding to CTLA-4 inhibition. 42 Our GSEA results suggest that eosinophils could be influenced by cytokines released during ICI treatment.…”

Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab

“…First, there have been no reports of a distinctive syndrome or health failure across several eosinophil-deficient mice strains under ordinary laboratory conditions [69,[76][77][78]. While some studies have reported that eosinophils have no tumoricidal activity [79,80], preclinical models of inducible or transplantable tumors have suggested a role for eosinophils in tumor regression and an increase in tumor incidence in the absence of eosinophils [81][82][83]. Other preclinical studies have examined the potential mechanisms linking eosinophils to cancer, with a particular focus on IL-5.…”