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 language | English |
|---|---|
| Pages (from-to) | 5555-5571 |
| Number of pages | 17 |
| Journal | Cancer Research |
| Volume | 81 |
| Issue number | 21 |
| DOIs | |
| State | Published - 1 Nov 2021 |
| Externally published | Yes |
Bibliographical note
Funding Information:A. Munitz reports grants from Israel Science Foundation, Binational Israel US Science Foundation, and grants and personal fees from GlaxoSmithKline, grants from Emerson Collective, Israel Cancer Research Fund, and grants and personal fees from AstraZeneca outside the submitted work. M.E. Rothenberg reports grants from National Institute of Allergy and Infectious Diseases and National Institutes of Health during the conduct of the study; and personal fees and other support from Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, and personal fees from Celgene, AstraZeneca, Arena Pharmaceuticals, GlaxoSmithKline, Guidepoint, Suvretta Capital Management, Teva Pharmaceuticals, Mapi Research Trust, and UpToDate outside the submitted work. M.J. Davis reports other support from CTX-One (Now Oncology One) outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
The authors thank all participants in the current study. The authors would like to thank Dr. Z. Gavish for performing part of the histological work. A. Munitz is supported by the US-Israel Binational Science Foundation (grant no. 2015163), by the Israel Science Foundation (grants no. 886/15 and 542/20), the Israel Cancer Research Fund, the Richard Eimert Research Fund on Solid Tumors (TAU), the Israel Cancer Association Avraham Rotstein Donation, the Cancer Biology Research Center (TAU), the Emerson Collective and GSK Investigator Supported Studies Program.
Publisher Copyright:
© 2021 American Association for Cancer Research
