Ovarian cancer-derived IL-4 promotes immunotherapy resistance

Gurkan Mollaoglu; Alexander Tepper; Chiara Falcomatà; Hunter T Potak; Luisanna Pia; Angelo Amabile; Jaime Mateus-Tique; Noam Rabinovich; Matthew D Park; Nelson M LaMarche; Rachel Brody; Lindsay Browning; Jia-Ren Lin; Dmitriy Zamarin; Peter K Sorger; Sandro Santagata; Miriam Merad; Alessia Baccarini; Brian D Brown

doi:10.1016/j.cell.2024.10.006

Ovarian cancer-derived IL-4 promotes immunotherapy resistance

Cell. 2024 Oct 30:S0092-8674(24)01154-1. doi: 10.1016/j.cell.2024.10.006. Online ahead of print.

Authors

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
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.

Abstract

Grants and funding