Metastasis-entrained eosinophils enhance lymphocyte-mediated antitumor immunity

Sharon Grisaru-Tal, Shai Dulberg, Lir Beck, Chunyan Zhang, Michal Itan, Soroor Hediyeh-Zadeh, Julie Caldwell, Perri Rozenberg, Avishay Dolitzky, Shmuel Avlas, Inbal Hazut, Yaara Gordon, Ophir Shani, Shlomo Tsuriel, Motti Gerlic, Neta Erez, Nicolas Jacquelot, Gabrielle T. Belz, Marc E. Rothenberg, Melissa J. DavisHua Yu, Tamar Geiger, Asaf Madi, Ariel Munitz

Research output: Contribution to journalArticlepeer-review

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, TNFa/IFNg-activated eosinophils facilitated CD4þ and CD8þ 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.

Original languageEnglish
Pages (from-to)5555-5571
Number of pages17
JournalCancer Research
Volume81
Issue number21
DOIs
StatePublished - 1 Nov 2021

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