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. Davis; Hua Yu; Tamar Geiger; Asaf Madi; Ariel Munitz

doi:10.1158/0008-5472.CAN-21-0839

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 journal › Article › peer-review

56 Scopus citations

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 CD4^þ and CD8^þ 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	https://doi.org/10.1158/0008-5472.CAN-21-0839
State	Published - 1 Nov 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 American Association for Cancer Research

Funding

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. 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.

Funders	Funder number
Cancer Biology Research Center
Emerson Collective
Emerson Collective, Israel Cancer Research Fund
Mapi Research Trust
Richard Eimert Research Fund on Solid Tumors
National Institutes of Health
National Institute of Allergy and Infectious Diseases
Israel Cancer Research Fund
AstraZeneca
Teva Pharmaceutical Industries
United States-Israel Binational Science Foundation	2015163
Israel Cancer Association
Israel Science Foundation	886/15, 542/20
Tel Aviv University

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10.1158/0008-5472.CAN-21-0839

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Grisaru-Tal, S., Dulberg, S., Beck, L., Zhang, C., Itan, M., Hediyeh-Zadeh, S., Caldwell, J., Rozenberg, P., Dolitzky, A., Avlas, S., Hazut, I., Gordon, Y., Shani, O., Tsuriel, S., Gerlic, M., Erez, N., Jacquelot, N., Belz, G. T., Rothenberg, M. E., ... Munitz, A. (2021). Metastasis-entrained eosinophils enhance lymphocyte-mediated antitumor immunity. Cancer Research, 81(21), 5555-5571. https://doi.org/10.1158/0008-5472.CAN-21-0839

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title = "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, TNFa/IFNg-activated eosinophils facilitated CD4{\th} and CD8{\th} 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.",

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

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Grisaru-Tal, S, Dulberg, S, Beck, L, Zhang, C, Itan, M, Hediyeh-Zadeh, S, Caldwell, J, Rozenberg, P, Dolitzky, A, Avlas, S, Hazut, I, Gordon, Y, Shani, O, Tsuriel, S, Gerlic, M, Erez, N, Jacquelot, N, Belz, GT, Rothenberg, ME, Davis, MJ, Yu, H, Geiger, T, Madi, A & Munitz, A 2021, 'Metastasis-entrained eosinophils enhance lymphocyte-mediated antitumor immunity', Cancer Research, vol. 81, no. 21, pp. 5555-5571. https://doi.org/10.1158/0008-5472.CAN-21-0839

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T1 - Metastasis-entrained eosinophils enhance lymphocyte-mediated antitumor immunity

AU - Grisaru-Tal, Sharon

AU - Dulberg, Shai

AU - Beck, Lir

AU - Zhang, Chunyan

AU - Itan, Michal

AU - Hediyeh-Zadeh, Soroor

AU - Caldwell, Julie

AU - Rozenberg, Perri

AU - Dolitzky, Avishay

AU - Avlas, Shmuel

AU - Hazut, Inbal

AU - Gordon, Yaara

AU - Shani, Ophir

AU - Tsuriel, Shlomo

AU - Gerlic, Motti

AU - Erez, Neta

AU - Jacquelot, Nicolas

AU - Belz, Gabrielle T.

AU - Rothenberg, Marc E.

AU - Davis, Melissa J.

AU - Yu, Hua

AU - Geiger, Tamar

AU - Madi, Asaf

AU - Munitz, Ariel

PY - 2021/11/1

Y1 - 2021/11/1

N2 - 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.

AB - 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.

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SN - 0008-5472

VL - 81

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EP - 5571

JO - Cancer Research

JF - Cancer Research

IS - 21

ER -

Metastasis-entrained eosinophils enhance lymphocyte-mediated antitumor immunity

Abstract

Bibliographical note

Funding

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