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. 2023 Jan 9;41(1):106-123.e10.
doi: 10.1016/j.ccell.2022.11.014. Epub 2022 Dec 15.

IL-5-producing CD4+ T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer

Olga S Blomberg  1 , Lorenzo Spagnuolo  2 , Hannah Garner  2 , Leonie Voorwerk  3 , Olga I Isaeva  4 , Ewald van Dyk  5 , Noor Bakker  2 , Myriam Chalabi  6 , Chris Klaver  3 , Maxime Duijst  3 , Kelly Kersten  3 , Marieke Brüggemann  3 , Dorien Pastoors  2 , Cheei-Sing Hau  2 , Kim Vrijland  2 , Elisabeth A M Raeven  2 , Daphne Kaldenbach  2 , Kevin Kos  1 , Inna S Afonina  7 , Paulien Kaptein  8 , Louisa Hoes  9 , Willemijn S M E Theelen  10 , Paul Baas  10 , Emile E Voest  9 , Rudi Beyaert  7 , Daniela S Thommen  8 , Lodewyk F A Wessels  11 , Karin E de Visser  12 , Marleen Kok  13
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Free article

IL-5-producing CD4+ T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer

Olga S Blomberg et al. Cancer Cell. .
Free article

Abstract

Immune checkpoint blockade (ICB) has heralded a new era in cancer therapy. Research into the mechanisms underlying response to ICB has predominantly focused on T cells; however, effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. Here, we combine unbiased analysis of blood and tumors from metastatic breast cancer patients treated with ICB with mechanistic studies in mouse models of breast cancer. We observe an increase in systemic and intratumoral eosinophils in patients and mice responding to ICB treatment. Mechanistically, ICB increased IL-5 production by CD4+ T cells, stimulating elevated eosinophil production from the bone marrow, leading to systemic eosinophil expansion. Additional induction of IL-33 by ICB-cisplatin combination or recombinant IL-33 promotes intratumoral eosinophil infiltration and eosinophil-dependent CD8+ T cell activation to enhance ICB response. This work demonstrates the critical role of eosinophils in ICB response and provides proof-of-principle for eosinophil engagement to enhance ICB efficacy.

Keywords: CD4(+) T cells; IL-33; IL-5; breast cancer; eosinophils; immune checkpoint blockade; myeloid cells.

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Conflict of interest statement

Declaration of interests O.S.B., H.G., L.S., L.V., O.I.I., E.v.D., N.B., C.K., M.D., K. Kersten, M.B., D.P., C.-S.H., K.V., E.A.M.R., D.K., L.H., K. Kos, I.S.A., P.K., R.B., and D.S.T. have no competing interests to declare. M.C. reports funding to the institute from BMS and Roche/Genentech and an advisory role for BMS, outside the submitted work. W.S.M.E.T. reports receiving grants from MSD during the conduct of the PEMBRO-RT trial. P.B. reports receiving grants and medication delivery from MSD during the conduct of the PEMBRO-RT trial as well as grants and consultancy fees from BMS outside the submitted work. E.E.V. is legally responsible for all contracts with pharmaceutical companies at the NKI and reports research funding from BMS, outside the submitted work. L.F.A.W. reports funding to the institute from Genmab BV. K.E.d.V. reports research funding from Roche/Genentech and is consultant for Macomics, outside the scope of this work. M.K. reports funding to the institute from BMS, Roche/Genentech, AZ, and an advisory role for BMS, Roche, MSD, and Daiichi Sankyo, outside the submitted work.

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