Ovarian cancer-derived IL-4 promotes immunotherapy resistance

Gurkan Mollaoglu¹, Alexander Tepper², Chiara Falcomatà², Hunter T Potak², Luisanna Pia², Angelo Amabile², Jaime Mateus-Tique², Noam Rabinovich³, Matthew D Park⁴, Nelson M LaMarche⁴, Rachel Brody⁵, Lindsay Browning⁶, Jia-Ren Lin⁷, Dmitriy Zamarin⁸, Peter K Sorger⁷, Sandro Santagata⁹, Miriam Merad⁴, Alessia Baccarini¹⁰, Brian D Brown¹¹

Affiliations

¹ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ R&A Data, New York, NY, USA.
⁴ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
⁸ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
¹⁰ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: alessia.baccarini@mssm.edu.
¹¹ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: brian.brown@mssm.edu.

PMID: 39481380
PMCID: PMC11682930 (available on 2025-12-26)
DOI: 10.1016/j.cell.2024.10.006

Ovarian cancer-derived IL-4 promotes immunotherapy resistance

Gurkan Mollaoglu et al. Cell. 2024.

. 2024 Dec 26;187(26):7492-7510.e22.

doi: 10.1016/j.cell.2024.10.006. Epub 2024 Oct 30.

Authors

Affiliations

¹ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ R&A Data, New York, NY, USA.
⁴ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
⁸ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
¹⁰ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: alessia.baccarini@mssm.edu.
¹¹ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: brian.brown@mssm.edu.

PMID: 39481380
PMCID: PMC11682930 (available on 2025-12-26)
DOI: 10.1016/j.cell.2024.10.006

Abstract

Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.

Keywords: CCL7; IL-4; Perturb-map; immunotherapy; intratumoral heterogeneity; macrophages; multiplex imaging; ovarian cancer; spatial CRISPR screens; spatial genomics; tumor immunology; tumor microenvironment; tumor neighborhood; type 2 immunity.

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Conflict of interest statement

Declaration of interests B.D.B. has a patent application on the Pro-Codes, which have been licensed to Immunai and Noetik. P.K.S. is co-founder of Glencoe Software and member of the SAB for RareCyte, NanoString, and Montai Health; he holds equity in Glencoe and RareCyte. N.R. is the founder of R&A Data.

References

1. Konstantinopoulos PA, and Matulonis UA (2023). Clinical and translational advances in ovarian cancer therapy. Nat Cancer, 1–19. 10.1038/s43018-023-00617-9. - DOI - PubMed
1. Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, Raspagliesi F, Sonke GS, Birrer M, Provencher DM, et al. (2019). Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Annals of Oncology 30, 1080–1087. 10.1093/annonc/mdz135. - DOI - PubMed
1. Varga A, Piha-Paul S, Ott PA, Mehnert JM, Berton-Rigaud D, Morosky A, Yang P, Ruman J, and Matei D (2019). Pembrolizumab in patients with programmed death ligand 1–positive advanced ovarian cancer: Analysis of KEYNOTE-028. Gynecologic Oncology 152, 243–250. 10.1016/j.ygyno.2018.11.017. - DOI - PubMed
1. Odunsi K (2017). Immunotherapy in ovarian cancer. Annals of Oncology 28, viii1–viii7. 10.1093/annonc/mdx444. - DOI - PMC - PubMed
1. Kandalaft LE, Dangaj Laniti D, and Coukos G (2022). Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation. Nat Rev Cancer 22, 640–656. 10.1038/s41568-022-00503-z. - DOI - PubMed

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Ovarian cancer-derived IL-4 promotes immunotherapy resistance

Affiliations

Ovarian cancer-derived IL-4 promotes immunotherapy resistance

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases