Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity

Abstract

The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein–coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ–activated eosinophils facilitated CD4+ and CD8+ T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics. Significance: These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer.

Transcriptional Profiling of Mouse Eosinophils Identifies Distinct Gene Signatures Following Cellular Activation

“…For example, the surface markers CD101 and CD34 were specifically upregulated in Type 2 eosinophils. CD101 expression was shown to be increased in eosinophils that infiltrate the lungs of allergen-challenged mice and upon infiltration of eosinophils to metastatic lungs ( 12 , 13 ). Furthermore, Cd34 -/- eosinophils displayed decreased movement in vitro and it was shown that CD34 is required for the influx of eosinophils to the gastrointestinal tract and following allergen challenge to the lungs ( 36 , 45 ).…”

“…In addition, while not many studies assessed the effects of IFN-γ on eosinophils, IFN-γ was shown to “prime” eosinophil responses to IL-5 and GM-CSF ( 48 ). In addition, several studies have shown that IFN-γ activates eosinophils to secrete chemokines such as CXCL9 and CXCL10 ( 13 , 49 ). This is consistent with our findings showing that IFN-γ primes eosinophils to innate immune stimulation and is capable of inducing chemokine secretion as well.…”

“…For example, eosinophils were shown to regulate Th1 responses in response to gastric infection via IFN-g-dependent upregulation of CD274 (51). CD274 expression was also increased in colonic tumor-associated eosinophils and metastasis-entrained eosinophils, which were both characterized by an IFN-g signature (13,29). Furthermore, the ability of Type 1 eosinophils to upregulate CD80 and CD86, likely enables them to act as antigen presenting cells.…”

“…These subsets differed in their transcriptional profile, surface phenotype (Siglec-F int /CD62 + /CD101 low vs. Siglec-F hi /CD62 - /CD101 hi ) anatomical location (parenchymal vs. peribronchial), nuclear morphology (ring-shaped vs. segmented), and dependence on IL-5, as well as their ability to down-modulate Type 2 immune responses ( 12 ). In contrast, we have recently shown that in the lungs of mice with experimental breast cancer metastasis, these eosinophil populations display no transcriptional difference ( 13 ). Thus, it is currently unknown whether these markers represent distinct eosinophil subtypes or rather a continuum of eosinophil activation states.…”

Development and Validation of a 7-Gene Inflammatory Signature Forecasts Prognosis and Diverse Immune Landscape in Lung Adenocarcinoma

“…The role of eosinophils in tumors is controversial ( Guerra et al, 2020 ). Interestingly, recent studies have found that eosinophils have antitumor activity in lung metastases and have anti-metastatic functions ( Grisaru-Tal et al, 2021 ; Schuijs et al, 2020 ). In a word, the immune cells above are potentially involved in the regulation of immune response in LUAD development, leading to a poor survival outcome in the high-risk group.…”