Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Eosinophil–lymphocyte interactions in the tumor microenvironment and cancer immunotherapy

Abstract

Eosinophils are important effector cells and therapeutic targets in allergic diseases. Emerging data indicate that eosinophils infiltrate a variety of solid tumor types and have pleiotropic activities by at least two non-mutually exclusive mechanisms: direct interactions with tumor cells, and intricate cross-talk with lymphocytes. In light of the immune checkpoint inhibition revolution in cancer therapy, we review eosinophil–lymphocyte interactions in the tumor microenvironment. We also analyze potential interactions between eosinophils and lymphocyte subsets, including T cells, natural killer cells and innate lymphoid cells. We provide perspectives on the consequences of these interactions and how eosinophils are accessory cells that can affect the response to various forms of T cell-mediated immunotherapies and might be therapeutically targeted to improve cancer immunotherapy.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Eosinophil–innate lymphoid cell interactions.
Fig. 2: Eosinophil–T cell interactions.
Fig. 3: Eosinophils as biomarkers and accessory cells in cancer immunotherapy.

References

  1. Jacobsen, E. A. et al. Eosinophil knockout humans: uncovering the role of eosinophils through eosinophil-directed biological therapies. Annu. Rev. Immunol. 39, 719–757 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Reinbach, G. Ueber das Verhalten der Leukocyten bei malignen Tumoren. Arch. Klin. Chir. Arch. Klin. Chir. 46, 486–562 (1893).

    Google Scholar 

  3. Grisaru-Tal, S. et al. Primary tumors from mucosal barrier organs drive unique eosinophil infiltration patterns and clinical associations. Oncoimmunology 10, 1859732 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Grisaru-Tal, S., Itan, M., Klion, A. D. & Munitz, A. A new dawn for eosinophils in the tumour microenvironment. Nat. Rev. Cancer 20, 594–607 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Jacquelot, N., Seillet, C., Vivier, E. & Belz, G. T. Innate lymphoid cells and cancer. Nat. Immunol. 23, 371–379 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Rodriguez-Rodriguez, N., Gogoi, M. & McKenzie, A. N. J. Group 2 innate lymphoid cells: team players in regulating asthma. Annu. Rev. Immunol. 39, 167–198 (2021).

    Article  CAS  PubMed  Google Scholar 

  7. Nussbaum, J. C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Maggi, E., Veneziani, I., Moretta, L., Cosmi, L. & Annunziato, F. Group 2 innate lymphoid cells: a double-edged sword in cancer? Cancers 12, 3452 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  9. Ikutani, M. et al. Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity. J. Immunol. 188, 703–713 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Jacquelot, N. et al. Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma. Nat. Immunol. 22, 851–864 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dankort, D. et al. BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nat. Genet. 41, 544–552 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dougan, M., Dranoff, G. & Dougan, S. K. GM-CSF, IL-3 and IL-5 family of cytokines: regulators of inflammation. Immunity 50, 796–811 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Martin, N. T. & Martin, M. U. Interleukin 33 is a guardian of barriers and a local alarmin. Nat. Immunol. 17, 122–131 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Lucarini, V. et al. IL-33 restricts tumor growth and inhibits pulmonary metastasis in melanoma-bearing mice through eosinophils. Oncoimmunology 6, e1317420 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Gao, K. et al. Transgenic expression of IL-33 activates CD8+ T cells and NK cells and inhibits tumor growth and metastasis in mice. Cancer Lett. 335, 463–471 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Andreone, S. et al. IL-33 promotes CD11b/CD18-mediated adhesion of eosinophils to cancer cells and synapse-polarized degranulation leading to tumor cell killing. Cancers 11, 1664 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  17. Brusilovsky, M. et al. Environmental allergens trigger type 2 inflammation through ripoptosome activation. Nat. Immunol. 22, 1316–1326 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Munitz, A. et al. 2B4 (CD244) is expressed and functional on human eosinophils. J. Immunol. 174, 110–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Munitz, A. et al. The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF and eotaxin on human peripheral blood eosinophils. Blood 107, 1996–2003 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Pesce, S. et al. The innate immune cross-talk between NK cells and eosinophils is regulated by the interaction of natural cytotoxicity receptors with eosinophil surface ligands. Front. Immunol. 8, 510 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Qi, L. et al. Interleukin-33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development. Int. J. Cancer 146, 1421–1434 (2020).

    Article  CAS  PubMed  Google Scholar 

  22. O’Flaherty, S. M. et al. TLR-stimulated eosinophils mediate recruitment and activation of NK cells in vivo. Scand. J. Immunol. 85, 417–424 (2017).

    Article  PubMed  CAS  Google Scholar 

  23. Schuijs, M. J. et al. ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung. Nat. Immunol. 21, 998–1009 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tay, R. E., Richardson, E. K. & Toh, H. C. Revisiting the role of CD4+ T cells in cancer immunotherapy—new insights into old paradigms. Cancer Gene Ther. 28, 5–17 (2021).

    Article  CAS  PubMed  Google Scholar 

  26. Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Oh, D. Y. & Fong, L. Cytotoxic CD4+ T cells in cancer: expanding the immune effector toolbox. Immunity 54, 2701–2711 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Grisaru-Tal, S. et al. Metastasis-entrained eosinophils enhance lymphocyte-mediated antitumor immunity. Cancer Res. 81, 5555–5571 (2021).

    Article  CAS  PubMed  Google Scholar 

  29. Mattes, J. et al. Immunotherapy of cytotoxic T cell-resistant tumors by T helper 2 cells: an eotaxin and STAT6-dependent process. J. Exp. Med. 197, 387–393 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hung, K. et al. The central role of CD4+ T cells in the antitumor immune response. J. Exp. Med. 188, 2357–2368 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Reichman, H. et al. Activated eosinophils exert antitumorigenic activities in colorectal cancer. Cancer Immunol. Res. 7, 388–400 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Dolitzky, A. et al. Transcriptional profiling of mouse eosinophils identifies distinct gene signatures following cellular activation. Front. Immunol. 12, 802839 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Carretero, R. et al. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8+ T cells. Nat. Immunol. 16, 609–617 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Akuthota, P., Wang, H. B., Spencer, L. A. & Weller, P. F. Immunoregulatory roles of eosinophils: a new look at a familiar cell. Clin. Exp. Allergy 38, 1254–1263 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Munitz, A. et al. CD48 is an allergen and IL-3-induced activation molecule on eosinophils. J. Immunol. 177, 77–83 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Arnold, I. C. et al. Eosinophils suppress TH1 responses and restrict bacterially induced gastrointestinal inflammation. J. Exp. Med. 215, 2055–2072 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Woerly, G. et al. Expression of CD28 and CD86 by human eosinophils and role in the secretion of type 1 cytokines (interleukin 2 and interferon gamma): inhibition by immunoglobulin a complexes. J. Exp. Med. 190, 487–495 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Onyema, O. O. et al. Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction. JCI Insight 4, e128241 (2019).

    Article  PubMed Central  Google Scholar 

  39. Lucey, D. R., Nicholson-Weller, A. & Weller, P. F. Mature human eosinophils have the capacity to express HLA-DR. Proc. Natl Acad. Sci. USA 86, 1348–1351 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hansel, T. T. et al. Sputum eosinophils from asthmatics express ICAM-1 and HLA-DR. Clin. Exp. Immunol. 86, 271–277 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Akuthota, P., Wang, H. & Weller, P. F. Eosinophils as antigen-presenting cells in allergic upper airway disease. Curr. Opin. Allergy Clin. Immunol. 10, 14–19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gurtner, A. et al. Single-cell RNA sequencing unveils intestinal eosinophil development and specialization. Preprint at bioRxiv https://doi.org/10.1101/2021.10.27.466053 (2021).

  43. Lee, J. J. et al. Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305, 1773–1776 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Arnold, I. C. et al. The GM-CSF–IRF5 signaling axis in eosinophils promotes antitumor immunity through activation of type 1 T cell responses. J. Exp. Med. 217, e20190706 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jia, S., Li, W., Liu, P. & Xu, L. X. A role of eosinophils in mediating the anti-tumour effect of cryo-thermal treatment. Sci. Rep. 9, 13214 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Fallegger, A. et al. TGF-beta production by eosinophils drives the expansion of peripherally induced neuropilin RORγt+ regulatory T cells during bacterial and allergen challenge. Mucosal. Immunol. 15, 504–514 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zaynagetdinov, R. et al. Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment. Cancer Res. 75, 1624–1634 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Webster, R. M. The immune checkpoint inhibitors: where are we now? Nat. Rev. Drug Discov. 13, 883–884 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Simon, H. U. et al. Interleukin-2 primes eosinophil degranulation in hypereosinophilia and Wells’ syndrome. Eur. J. Immunol. 33, 834–839 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Sosman, J. A. et al. Evidence for eosinophil activation in cancer patients receiving recombinant interleukin-4: effects of interleukin-4 alone and following interleukin-2 administration. Clin. Cancer Res. 1, 805–812 (1995).

    CAS  PubMed  Google Scholar 

  53. Ellem, K. A. et al. A case report: immune responses and clinical course of the first human use of granulocyte/macrophage-colony-stimulating-factor-transduced autologous melanoma cells for immunotherapy. Cancer Immunol. Immunother. 44, 10–20 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Gebhardt, C. et al. Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin. Cancer Res. 21, 5453–5459 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Martens, A. et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin. Cancer Res. 22, 2908–2918 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lang, B. M. et al. Long-term survival with modern therapeutic agents against metastatic melanoma—vemurafenib and ipilimumab in a daily life setting. Med. Oncol. 35, 24 (2018).

    Article  CAS  PubMed  Google Scholar 

  57. Simon, S. C. S. et al. Eosinophil accumulation predicts response to melanoma treatment with immune checkpoint inhibitors. Oncoimmunology 9, 1727116 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Cruikshank, W. & Center, D. M. Modulation of lymphocyte migration by human lymphokines. II. Purification of a lymphotactic factor (LCF). J. Immunol. 128, 2569–2574 (1982).

    CAS  PubMed  Google Scholar 

  59. Zheng, X. et al. CTLA4 blockade promotes vessel normalization in breast tumors via the accumulation of eosinophils. Int. J. Cancer 146, 1730–1740 (2020).

    Article  CAS  PubMed  Google Scholar 

  60. Moreira, A., Leisgang, W., Schuler, G. & Heinzerling, L. Eosinophilic count as a biomarker for prognosis of melanoma patients and its importance in the response to immunotherapy. Immunotherapy 9, 115–121 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Weide, B. et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin. Cancer Res. 22, 5487–5496 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Alves, A., Dias, M., Campainha, S. & Barroso, A. Peripheral blood eosinophilia may be a prognostic biomarker in non-small cell lung cancer patients treated with immunotherapy. J. Thorac. Dis. 13, 2716–2727 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Herrmann, T. et al. Eosinophil counts as a relevant prognostic marker for response to nivolumab in the management of renal cell carcinoma: a retrospective study. Cancer Med. 10, 6705–6713 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ghebeh, H., Elshenawy, M. A., AlSayed, A. D. & Al-Tweigeri, T. Peripheral blood eosinophil count is associated with response to chemoimmunotherapy in metastatic triple-negative breast cancer. Immunotherapy 14, 189–199 (2022).

    CAS  PubMed  Google Scholar 

  65. Nishikawa, D. et al. Eosinophil prognostic scores for patients with head and neck squamous cell carcinoma treated with nivolumab. Cancer Sci. 112, 339–346 (2021).

    Article  CAS  PubMed  Google Scholar 

  66. Hollande, C. et al. Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth. Nat. Immunol. 20, 257–264 (2019).

    Article  CAS  PubMed  Google Scholar 

  67. Sterner, R. C. & Sterner, R. M. CAR T cell therapy: current limitations and potential strategies. Blood Cancer J. 11, 69 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Jia, Q. et al. Peripheral eosinophil counts predict efficacy of anti-CD19 CAR-T cell therapy against B-lineage non-Hodgkin lymphoma. Theranostics 11, 4699–4709 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cheng, J. N. et al. Radiation-induced eosinophils improve cytotoxic T lymphocyte recruitment and response to immunotherapy. Sci. Adv. 7, eabc7609 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lai, W. et al. Human pluripotent stem cell-derived eosinophils reveal potent cytotoxicity against solid tumors. Stem Cell Rep. 16, 1697–1704 (2021).

    Article  CAS  Google Scholar 

  71. Li, M. O. et al. Innate immune cells in the tumor microenvironment. Cancer Cell 39, 725–729 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Rafei-Shamsabadi, D., Lehr, S., Behrens, M. & Meiss, F. Additive intralesional interleukin-2 improves progression-free survival in a distinct subgroup of melanoma patients with prior progression under immunotherapy. Cancers 14, 540 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hude, I. et al. Leucocyte and eosinophil counts predict progression-free survival in relapsed or refractory classical Hodgkin lymphoma patients treated with PD1 inhibition. Br. J. Haematol. 181, 837–840 (2018).

    Article  PubMed  Google Scholar 

  74. Furubayashi, N. et al. The association of clinical outcomes with posttreatment changes in the relative eosinophil counts and neutrophil-to-eosinophil ratio in patients with advanced urothelial carcinoma treated with pembrolizumab. Cancer Manag. Res. 13, 8049–8056 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants and fellowships to A.M. from the US-Israel Bi-national Science Foundation (grant no. 2015163, to A.M. and M.E.R.), Israel Science Foundation (grant nos. 886/15 and 542/20), Israel Cancer Research Fund, Richard Eimert Research Fund on Solid Tumors, Israel Cancer Association, Dotan Hemato Oncology fund, Cancer Biology Research Center, Tel Aviv University, The Tel Aviv University Faculty of Medicine Recanati Fund and Azrieli Foundation Canada-Israel. M.E.R. was further supported by the National Institutes of Health (R37 AI045898, R01 AI124355, U19 AI070235 and P30 DK078392; Gene and Protein Expression Core), Campaign Urging Research for Eosinophilic Disease (CURED) and Sunshine Charitable Foundation and its supporters, D. A. Bunning and D. G. Bunning.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ariel Munitz.

Ethics declarations

Competing interests

A.M. is a consultant and/or international advisory board member for GSK, AstraZeneca, Sanofi, Oravax and Sartorious and is an inventor of patents owned by the Tel Aviv University. M.E.R. is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex Therapeutics, Nextstone One, Bristol Myers Squibb, AstraZeneca, Ellodi Pharma, GSK, Regeneron/Sanofi, Revolo Biotherapeutics and Guidepoint; has an equity interest in the first seven companies listed and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust) and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital. S.G.-T. declares no competing interests.

Peer review

Peer review information

Nature Immunology thanks Viktor Umansky and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Nick Bernard, in collaboration with the Nature Immunology team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Grisaru-Tal, S., Rothenberg, M.E. & Munitz, A. Eosinophil–lymphocyte interactions in the tumor microenvironment and cancer immunotherapy. Nat Immunol 23, 1309–1316 (2022). https://doi.org/10.1038/s41590-022-01291-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-022-01291-2

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer