The GM-CSF–IRF5 signaling axis in eosinophils promotes antitumor immunity through activation of type 1 T cell responses

Abstract

The depletion of eosinophils represents an efficient strategy to alleviate allergic asthma, but the consequences of prolonged eosinophil deficiency for human health remain poorly understood. We show here that the ablation of eosinophils severely compromises antitumor immunity in syngeneic and genetic models of colorectal cancer (CRC), which can be attributed to defective Th1 and CD8+ T cell responses. The specific loss of GM-CSF signaling or IRF5 expression in the eosinophil compartment phenocopies the loss of the entire lineage. GM-CSF activates IRF5 in vitro and in vivo and can be administered recombinantly to improve tumor immunity. IL-10 counterregulates IRF5 activation by GM-CSF. CRC patients whose tumors are infiltrated by large numbers of eosinophils also exhibit robust CD8 T cell infiltrates and have a better prognosis than patients with eosinophillow tumors. The combined results demonstrate a critical role of eosinophils in tumor control in CRC and introduce the GM-CSF–IRF5 axis as a critical driver of the antitumor activities of this versatile cell type.

Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

“…Distinctive transcriptional and proteomic profiles are also observed in eosinophils within tissue microdomains. Histologic surveys suggest tumor-associated eosinophilia tends to be associated with improved prognoses in patients with solid tumors, particularly in gastric and colorectal cancers [73]. Eosinophils are actively recruited to developing tumors and promote anti-tumor immunity in inflammation-induced and genetic spontaneous mouse models of colorectal cancer [73,74].…”

“…Histologic surveys suggest tumor-associated eosinophilia tends to be associated with improved prognoses in patients with solid tumors, particularly in gastric and colorectal cancers [73]. Eosinophils are actively recruited to developing tumors and promote anti-tumor immunity in inflammation-induced and genetic spontaneous mouse models of colorectal cancer [73,74]. The tumor microenvironment supports prolonged eosinophil survival [74], and intratumor eosinophils exhibit pro-inflammatory gene and proteome signatures distinct from those of colonic eosinophils from tumor-adjacent tissue.…”

“…The tumor microenvironment supports prolonged eosinophil survival [74], and intratumor eosinophils exhibit pro-inflammatory gene and proteome signatures distinct from those of colonic eosinophils from tumor-adjacent tissue. The intratumor eosinophil transcriptome is characterized by genes involved in interferon signaling, enzymatic regulators of the extracellular matrix, and chemokines and cytokines implicated in recruitment of activated T cells [73,74]. The altered transcriptional profile of intratumor eosinophils was driven by granulocyte macrophage-colony stimulating factor (GM-CSF), and exogenous GM-CSF further enhanced the anti-tumor immune response [73].…”

“…The intratumor eosinophil transcriptome is characterized by genes involved in interferon signaling, enzymatic regulators of the extracellular matrix, and chemokines and cytokines implicated in recruitment of activated T cells [73,74]. The altered transcriptional profile of intratumor eosinophils was driven by granulocyte macrophage-colony stimulating factor (GM-CSF), and exogenous GM-CSF further enhanced the anti-tumor immune response [73]. Although multiple studies agree that intratumor eosinophils promote anti-tumor immunity, there are conflicting reports on the precise eosinophil-dependent mechanism(s), which may involve direct cytotoxic activities of eosinophils on tumor cells [74] and/or enhancing the Th1 anti-tumor immune response [73].…”

“…The altered transcriptional profile of intratumor eosinophils was driven by granulocyte macrophage-colony stimulating factor (GM-CSF), and exogenous GM-CSF further enhanced the anti-tumor immune response [73]. Although multiple studies agree that intratumor eosinophils promote anti-tumor immunity, there are conflicting reports on the precise eosinophil-dependent mechanism(s), which may involve direct cytotoxic activities of eosinophils on tumor cells [74] and/or enhancing the Th1 anti-tumor immune response [73]. The latter finding is particularly intriguing in light of the tendency of intestinal eosinophils to dampen Th17 and Th1 in the steady state [26], and within the context of bacterial infection [72], respectively, and further supports the broad immune plasticity of intestinal tissue eosinophils, shaped by the local microenvironment.…”